[go: up one dir, main page]

WO2025212991A1 - Rodent models of disease - Google Patents

Rodent models of disease

Info

Publication number
WO2025212991A1
WO2025212991A1 PCT/US2025/023109 US2025023109W WO2025212991A1 WO 2025212991 A1 WO2025212991 A1 WO 2025212991A1 US 2025023109 W US2025023109 W US 2025023109W WO 2025212991 A1 WO2025212991 A1 WO 2025212991A1
Authority
WO
WIPO (PCT)
Prior art keywords
human
genetically modified
gene
endogenous
hla
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/023109
Other languages
French (fr)
Inventor
Olivier HERBIN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Regeneron Pharmaceuticals Inc
Original Assignee
Regeneron Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Regeneron Pharmaceuticals Inc filed Critical Regeneron Pharmaceuticals Inc
Publication of WO2025212991A1 publication Critical patent/WO2025212991A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
    • A01K67/027—New or modified breeds of vertebrates
    • A01K67/0275—Genetically modified vertebrates, e.g. transgenic
    • A01K67/0278—Knock-in vertebrates, e.g. humanised vertebrates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/7051—T-cell receptor (TcR)-CD3 complex
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70539—MHC-molecules, e.g. HLA-molecules
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0636—T lymphocytes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
    • C12N9/22—Ribonucleases [RNase]; Deoxyribonucleases [DNase]
    • C12N9/222—Clustered regularly interspaced short palindromic repeats [CRISPR]-associated [CAS] enzymes
    • C12N9/226—Class 2 CAS enzyme complex, e.g. single CAS protein
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2207/00—Modified animals
    • A01K2207/12—Animals modified by administration of exogenous cells
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/07—Animals genetically altered by homologous recombination
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/07—Animals genetically altered by homologous recombination
    • A01K2217/072—Animals genetically altered by homologous recombination maintaining or altering function, i.e. knock in
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/15—Animals comprising multiple alterations of the genome, by transgenesis or homologous recombination, e.g. obtained by cross-breeding
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2227/00—Animals characterised by species
    • A01K2227/10—Mammal
    • A01K2227/105—Murine
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A01K2267/0306—Animal model for genetic diseases
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A01K2267/0306—Animal model for genetic diseases
    • A01K2267/0325—Animal model for autoimmune diseases
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A01K2267/035—Animal model for multifactorial diseases
    • A01K2267/0387—Animal model for diseases of the immune system
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2510/00—Genetically modified cells

Definitions

  • the first recombinant nucleic acid is at an endogenous classical MHC locus and/or replaces an endogenous classical MHC gene or portion thereof.
  • the rodent is homozygous for a replacement of the endogenous classical MHC gene or portion thereof with the first recombinant nucleic acid.
  • the genetically modified rodent is homozygous for a replacement of the endogenous IL15 gene with the human or humanized IL15 gene.
  • the human or humanized SIRPA gene is at an endogenous sirpa locus and/or replaces an endogenous sirpa gene.
  • the genetically modified rodent is homozygous for a replacement of the endogenous sirpa gene with the human or humanized SIRPA gene.
  • the human T cell is an activated effector T cell.
  • the genetically modified rodent as described herein further comprises an antigen that binds to the antigen presenting portion of the classical HLA molecule.
  • the recombinant human TCR variable domain binds the antigen presented in the context of the antigen presenting portion of the classical HLA.
  • the antigen is a gliadin peptide.
  • described herein is a method of making a rodent model of disease.
  • the recombinant nucleic acid that encodes the recombinant human TCR variable domain that binds the antigen presented in the context of an antigen presenting portion of the classical HLA molecule is operably linked to a non-human promoter (e.g., EF1 ⁇ promoter, spleen focus-forming virus (SFFV) promoter, etc.) that controls expression of the recombinant human TCR variable domain and/or a non-human regulatory element (e.g., Woodchuck posttranscriptional regulatory element (WPRE)) that enhances expression of the recombinant human TCR variable domain; comprises a non-human nucleic acid, e.g., a viral nucleic acid (e.g., viral nucleic acid encoding a 2A peptide (e.g., a T2A peptide, a P2A peptide, a F2A peptide, etc.), an adeno-
  • a non-human promoter e.
  • Figure 1 shows a schematic illustration, not to scale, of MHC class II I-E and I-A genes, showing knockout of the mouse locus using a hygromycin cassette in ES cells (MAID 5111), followed by introduction of a vector comprising humanized I-A ⁇ and I-A ⁇ (i.e., HLA- DQ ⁇ 1*02/H-2A ⁇ and HLA-DQ ⁇ 1*05/H-2A ⁇ chimeras, respectively) that replaces the hygromycin cassette with genes encoding chimeric human/mouse HLA-DQ2.5/H2-A.
  • a vector comprising humanized I-A ⁇ and I-A ⁇ (i.e., HLA- DQ ⁇ 1*02/H-2A ⁇ and HLA-DQ ⁇ 1*05/H-2A ⁇ chimeras, respectively) that replaces the hygromycin cassette with genes encoding chimeric human/mouse HLA-DQ2.5/H2-A.
  • the empty boxes or triangles are sequences of the human exons
  • the double lines are sequences of the human introns
  • the filled boxes or triangles are sequences of the mouse exons
  • single lines are sequences of mouse introns. Location of junctional sequences are indicated below each targeting vector diagram and presented in Table 2 and the Sequence Listing.
  • Figures 4A-4C demonstrate that ⁇ 1-gliadin CD8 + TCR T cells transferred into HLA-DQ2.5/H2-A mice (also knocked-in for human IL15 and human SIRPA on a Rag2 -/- /Il2rg -/- background) (see Figure 1) are activated after oral gavage with a synthetic peptide containing the ⁇ 1-gliadin sequence.
  • Figure 5A depicts a gene expression analysis (IFN ⁇ , Granzyme B, and CCL5) of the small intestine of HLA-DQ2.5/H2-A mice administered PBS vehicle or 5 mg of ⁇ 1/ ⁇ 2 gliadin- derived peptide as determined by TaqMan PCR.
  • Figure 5B shows serum expression analysis (IFN ⁇ , IL-2, and TNF- ⁇ ) of the small intestine of HLA-DQ2.5/H2-A mice administered PBS vehicle or 5 mg of ⁇ 1/ ⁇ 2 gliadin-derived peptide as determined by immunoassay.
  • the rodent is selected from a mouse, a rat, and a hamster. In one embodiment, the rodent is selected from the superfamily Muroidea. In one embodiment, the genetically modified rodent is from a family selected from Calomyscidae (e.g., mouse-like hamsters), Cricetidae (e.g., hamster, New World rats and mice, voles), Muridae (true mice and rats, gerbils, spiny mice, crested rats), Nesomyidae (climbing mice, rock mice, with-tailed rats, Malagasy rats and mice), Platacanthomyidae (e.g., spiny dormice), and Spalacidae (e.g., mole rates, bamboo rats, and zokors).
  • Calomyscidae e.g., mouse-like hamsters
  • Cricetidae e.g., hamster, New World rats and mice,
  • the genetically modified rodent is selected from a true mouse or rat (family Muridae), a gerbil, a spiny mouse, and a crested rat.
  • the rodent is selected from a mouse and a rat.
  • the rodent is a mouse.
  • rodent is a mouse of a C57BL strain selected from C57BL/A, C57BL/An, C57BL/GrFa, C57BL/KaLwN, C57BL/6, C57BL/6J, C57BL/6ByJ, C57BL/6NJ, C57BL/10, C57BL/10ScSn, C57BL/10Cr, and C57BL/Ola.
  • the genetically modified mouse is a mix of an aforementioned 129 strain and an aforementioned C57BL/6 strain.
  • the mouse is a mix of aforementioned 129 strains, or a mix of aforementioned BL/6 strains.
  • the 129 strain of the mix is a 129S6 (129/SvEvTac) strain.
  • the mouse is a BALB strain, e.g., BALB/c strain. In yet another embodiment, the mouse is a mix of a BALB strain and another aforementioned strain.
  • the rodent is a rat. In one embodiment, the rat is selected from a Wistar rat, an LEA strain, a Sprague Dawley strain, a Fischer strain, F344, F6, and Dark Agouti. In one embodiment, the rat strain is a mix of two or more strains selected from the group consisting of Wistar, LEA, Sprague Dawley, Fischer, F344, F6, and Dark Agouti.
  • MHC or HLA may be used interchangeably herein, and may refer to (a) associated complexes, e.g., an MHC class II complex comprising ⁇ and ⁇ chains, (b) individual MHC/HLA chains, e.g., an MHC class II ⁇ chain, and/or (c) fragments thereof, e.g., subunits or domains of the individual chains, e.g., the ⁇ 1 subunit of the ⁇ chain of an MHC class II complex.
  • associated complexes e.g., an MHC class II complex comprising ⁇ and ⁇ chains
  • individual MHC/HLA chains e.g., an MHC class II ⁇ chain
  • fragments thereof e.g., subunits or domains of the individual chains, e.g., the ⁇ 1 subunit of the ⁇ chain of an MHC class II complex.
  • MHC molecules are encoded by multiple loci that are found as a linked cluster of genes that spans about 4 Mb.
  • the MHC genes are found on chromosome 17, and for historical reasons are referred to as the histocompatibility 2 (H-2) genes.
  • H-2 histocompatibility 2
  • HLA human leukocyte antigen
  • class MHC or “classical HLA” refer to class I or class II MHC, e.g., HLA, molecules and/or genes encoding the same.
  • HLA class I genes are termed HLA-A, HLA-B, and HLA-C, whereas in mice they are the termed H2-D, H2-L and H2-K.
  • HLA-DP, HLA-DQ, and HLA-DR are termed H-2A and H-2E (often abbreviated as I-A and I-E, respectively).
  • An MHC class I molecule is an integral membrane protein comprising a glycoprotein heavy chain, also referred to herein as the ⁇ chain, which has three extracellular domains (i.e., ⁇ 1, ⁇ 2 and ⁇ 3) and two intracellular domains (i.e., a transmembrane domain (TM) and a cytoplasmic domain (CYT)).
  • the heavy chain is noncovalently associated with a soluble subunit called ⁇ 2 microglobulin ( ⁇ 2m or ⁇ 2M).
  • An MHC class II molecule or MHC class II protein is a heterodimeric integral membrane protein comprising one ⁇ chain and one ⁇ chain in noncovalent association.
  • MHC class I and II molecules comprise an antigen presenting portion, e.g., a peptide binding groove, peptide-binding cleft, etc.
  • Antigen presenting portion refers to the minimum amino acid sequence and/or structure of an MHC required for antigen binding and presentation.
  • An MHC class I molecule comprises an antigen presenting portion, e.g., a peptide binding groove, formed by the ⁇ 1 and ⁇ 2 domains of the heavy ⁇ chain that can stow a peptide of around 8-10 amino acids.
  • an antigen presenting portion e.g., a peptide binding groove
  • both classes of MHC bind a core of about 9 amino acids (e.g., 5 to 17 amino acids) within peptides
  • the open-ended nature of MHC class II antigen presenting portion e.g., the peptide binding groove; i.e., the ⁇ 1 domain of a class II MHC ⁇ polypeptide in association with the ⁇ 1 domain of a class II MHC ⁇ polypeptide
  • Peptides binding MHC class II usually vary between 13 and 17 amino acids in length, though shorter or longer lengths are not uncommon. As a result, peptides may shift within the MHC class II antigen presenting portion, e.g., peptide binding groove, changing which 9-mer sits directly within the groove at any given time.
  • the terms "antigen”, “epitope” and “antigenic determinant” as used interchangeably herein encompass any agent (e.g., protein, peptide, polysaccharide, glycoprotein, glycolipid, nucleotide, portions thereof, or combinations thereof) that, when introduced into an immunocompetent host is recognized by the immune system of the host and elicits an immune response by the host.
  • the T-cell receptor recognizes a peptide presented in the context of a major histocompatibility complex (MHC) as part of an immunological synapse.
  • MHC major histocompatibility complex
  • pMHC major histocompatibility complex
  • the peptide-MHC (pMHC) complex is recognized by TCR, with the peptide (antigenic determinant) and the TCR idiotype providing the specificity of the interaction.
  • the term “antigen” encompasses peptides presented in the context of MHCs, e.g., peptide-MHC complexes, e.g., pMHC complexes.
  • T cells bind antigens presented by an MHC through a T cell receptor (TCR) complex on the surface of the T cell.
  • TCR T cell receptor
  • T cell receptors are heterodimeric structures composed of two types of chains: an ⁇ (alpha) and ⁇ (beta) chain, or a ⁇ (gamma) and ⁇ (delta) chain.
  • the ⁇ chain is encoded by the nucleic acid sequence located within the ⁇ locus on human chromosome 14, which also encompasses the entire ⁇ locus, and the ⁇ chain is encoded by the nucleic acid sequence located within the ⁇ locus on human chromosome 7.
  • the majority of T cells have an ⁇ TCR; while a minority of T cells bear a ⁇ TCR.
  • T-cell receptor ⁇ and ⁇ polypeptides are linked to each other via a disulfide bond.
  • Each of the two polypeptides that make up the TCR contains an extracellular domain comprising constant and variable regions, a transmembrane domain, and a cytoplasmic tail (the transmembrane domain and the cytoplasmic tail also being a part of the constant region).
  • the variable region of the TCR determines its antigen specificity, and similar to immunoglobulins, comprises 3 complementary determining regions (CDRs), e.g., CDR1, CDR2, and CDR3.
  • CDRs complementary determining regions
  • T cell receptor variable gene loci e.g., TCR ⁇ and TCR ⁇ loci
  • TCR ⁇ and TCR ⁇ loci contain a number of unrearranged V(D)J segments (variable (V), joining (J), and in TCR ⁇ and ⁇ , diversity (D) segments).
  • TCR ⁇ variable gene locus undergoes rearrangement, such that the resultant TCR ⁇ variable domain is encoded by a specific combination of VJ segments (V ⁇ /J ⁇ sequence); and TCR ⁇ variable gene locus undergoes rearrangement, such that the resultant TCR ⁇ variable domain is encoded by a specific combination of VDJ segments (V ⁇ /D ⁇ /J ⁇ sequence).
  • the TCR ⁇ and ⁇ variable domains in particular the CDR1, CDR2, and CDR3 and more particularly the CDR3, provide the specificity with which the TCR binds an MHC.
  • nucleic acid encoding a TCR encompasses one or more nucleic acids encoding one or more subunits of a TCR, or a portion thereof.
  • a nucleic acid encoding a TCR variable domain e.g., comprising non-covalently complexed variable domains of TCR ⁇ and TCR ⁇ subunits, encompasses (i) a single nucleic acid encoding both the TCR ⁇ variable domain and TCR ⁇ variable domain, and (ii) more than one nucleic acid encoding the TCR ⁇ variable domain and TCR ⁇ variable domain, individually, e.g., a first nucleic acid encoding a TCR ⁇ variable domain and a second nucleic acid encoding a TCR ⁇ variable domain.
  • the TCR ⁇ and TCR ⁇ subunits of the gliadin-specific TCR are introduced on a single nucleic acid encoding both the TCR ⁇ variable domain and TCR ⁇ variable domain.
  • the activation of a T cell following engagement with a peptide-MHC can be determined by identifying one or more activation-induced marker.
  • An “activation-induced marker” or “AIM” is a marker that is expressed, or in which the expression is upregulated, after activation of a T cell.
  • T cell activation marker e.g., the activation induced marker
  • CD40L comprises CD40L.
  • CD40L may also be referred to as CD154.
  • the T cell activation marker e.g., the activation induced marker, comprises tumor necrosis factor receptor superfamily, member 9 (TNFRSF9).
  • TNFRSF9 is also referred to herein as CD137 and/or 4-1BB.
  • CD137/4-1BB refers to the molecule known in the art as CD137, 4-1BB, TNFRSF9, and the like, and the phrases “CD137,” “4-1BB,” “CD137/4-1BB,” and “TNFRSF9” may be used interchangeably.
  • CD137/4- 1BB is a transient T cell activation marker that is upregulated rapidly upon antigen-specific TCR engagement and remains expressed on cells for approximately 72 hours. In methods described herein, between 20-36 hours after exposure to an antigen appears to be the optimal time point for functional enrichment of CD137/4-1BB expression and detection.
  • the activation-induced marker comprises CD107.
  • CD107 may also be referred to as CD107a or LAMP1.
  • the activation-induced marker comprises interferon gamma (IFN ⁇ ), which may also be referred to as gamma interferon, IFNG, IFG, etc.
  • the activation-induced marker comprises programmed cell death 1, which may also be referred to as PD-1, PD1, CD279, and HPD-1.
  • the activation-induced marker comprises TNF Receptor Superfamily member 4, which may also be referred to as OX40 and/or CD134.
  • the activation-induced marker comprises interleukin-2 receptor alpha, which may also be referred to as IL-2R, IL-2R ⁇ , and/or CD25.
  • the activation-induced marker comprises CD69, which may also be referred to leukocyte surface antigen Leu-23 and/or MLR3.
  • the activation-induced marker comprises CD28, which may also be referred to Tp44 and/or T-cell specific surface glycoprotein.
  • the activation-induced marker comprises major histocompatibility complex class II DR, which may also be referred to as human leukocyte antigen class II DR and/or HLA-DR.
  • the activation-induced marker comprises C X C motif chemokine receptor (CX3CR1), which may also be referred to as IL-8 Receptor, IL-8R ⁇ , and/or CDw128a.
  • the activation-induced marker comprises TIM3, which may also be referred to as Hepatitis A Virus Cellular Receptor 2, T cell Membrane Protein 3, and/or CD366.
  • the activation-induced marker comprises lymphocyte activation gene 3 (LAG3), which may also be referred to as CD223.
  • the activation-induced marker comprises T cell Immunoreceptor with Ig and ITIM Domains (TIGIT), which may also be referred to as V-Set and Immunoglobulin Domain Containing Protein 9 (VSIG9) and/or V-Set and/or Transmembrane Domain Containing 3 (VSTM3).
  • the activation-induced marker comprises granzyme B (GZMB), which may also be referred to as C11; HLP; CCPI; CGL1; CSPB; SECT; CGL-1; CSP-B; CTLA1; CTSGL1.
  • the activation-induced marker comprises chemokine (C-C motif) ligand 5 (CCL5), which may also be referred to as SISd; eoCP; SCYA5; RANTES; TCP228; D17S136E; SIS-delta.
  • the activation-induced marker comprises Ki-67 protein, which may also be referred to as Ki67; KIA; MIB-; MIB-1; PPP1R105.
  • the activation-induced marker comprises ectonucleoside triphosphate diphosphohydrolase 3, which may also be referred to as CD39 and/or ENTPD1.
  • the AIM comprises inducible T cell costimulatory, which may also be referred to herein as ICOS and/or CD278.
  • groups of amino acids that have side chains with similar chemical properties include aliphatic side chains such as glycine, alanine, valine, leucine, and isoleucine; aliphatic-hydroxyl side chains such as serine and threonine; amide-containing side chains such as asparagine and glutamine; aromatic side chains such as phenylalanine, tyrosine, and tryptophan; basic side chains such as lysine, arginine, and histidine; acidic side chains such as aspartic acid and glutamic acid; and, sulfur-containing side chains such as cysteine and methionine.
  • aliphatic side chains such as glycine, alanine, valine, leucine, and isoleucine
  • aliphatic-hydroxyl side chains such as serine and threonine
  • amide-containing side chains such as asparagine and glutamine
  • aromatic side chains such as phenylalanine, tyrosine, and trypto
  • various portions of the chimeric or humanized protein of the invention may be operably linked to retain proper folding, processing, targeting, expression, and other functional properties of the protein in the cell. Unless stated otherwise, various domains of the chimeric or humanized protein of the invention are operably linked to each other.
  • antigen presenting portion of the classical HLA molecule comprises ⁇ 1, ⁇ 2, and ⁇ 3 domains of a classical HLA class I molecule, or ⁇ 1, ⁇ 2, ⁇ 1, and ⁇ 2 domains of a classical HLA class II molecule.
  • the nucleotide sequence, e.g., the recombinant nucleic acid, encoding the human or humanized MHC is present at an endogenous classical MHC locus and/or replaces an endogenous classical MHC gene or a portion thereof.
  • the genetically modified rodent is heterozygous for a replacement of the endogenous classical MHC gene or portion thereof with the nucleotide sequence, e.g., recombinant nucleic acid, encoding the human or humanized MHC molecule.
  • humanized refers to a molecule (e.g., a nucleic acid, protein, etc.) that was non-human in origin and for which a portion has been replaced with a corresponding portion of a corresponding human molecule in such a manner that the modified (e.g., humanized, chimeric, human/non-human, etc.) molecule retains its biological function and/or maintains the structure that performs the retained biological function.
  • a humanized molecule may be considered derived from a human molecule where the humanized molecule is encoded by a nucleotide comprising a nucleic acid sequence that encodes the human molecule (or a portion thereof).
  • human and the like encompasses molecules having only a human origin, e.g., human nucleotides or protein comprising only human nucleotide and amino acid sequences respectively.
  • the term “human(ized)” may be used to reflect that the human(ized) molecule may be (a) a human molecule or (b) a humanized molecule.
  • endogenous locus or “endogenous gene” refers to a genetic locus found in a parent or reference organism prior to introduction of a disruption, deletion, replacement, alteration, or modification as described herein. In some embodiments, an endogenous locus has a sequence found in nature. In some embodiments, an endogenous locus is a wild-type locus.
  • an endogenous locus is an engineered locus.
  • replacement in reference to gene replacement refers to placing exogenous genetic material at an endogenous genetic locus, thereby replacing all or a portion of the endogenous gene with an orthologous or homologous nucleic acid sequence.
  • the nucleotide sequence of the endogenous MHC II locus was replaced by a nucleotide sequence, e.g., recombinant nucleic acid, encoding a chimeric human/mouse MHC class II molecule, e.g., HLA-DQ2.5/H2-A.
  • the genetically modified rodent comprises a nucleotide sequence, e.g., a recombinant nucleic acid, encoding at least an antigen presenting portion of an HLA class I molecule (e.g., an HLA-B molecule) or an HLA class II molecule, (e.g., an HLA- DR1 molecule, an HLA-DR2 molecule, an HLA-DR3 molecule, an HLA-DR4 molecule, an HLA-DR13 molecule, an HLA-DR15 molecule, an HLA-DQ2 molecule, an HLA-DQ4 molecule, an HLA-DQ8 molecule, an HLA-DQ9 molecule), or any combination thereof.
  • an HLA class I molecule e.g., an HLA-B molecule
  • HLA class II molecule e.g., an HLA- DR1 molecule, an HLA-DR2 molecule, an HLA-DR3 molecule, an HLA-DR4 molecule
  • the invention provides a genetically modified non-human animal (e.g., mouse, rat, rabbit, etc.) that comprises in its genome a nucleotide sequence encoding a human or humanized MHC class I polypeptide.
  • the non-human animal may comprise in its genome a nucleotide sequence that encodes an MHC I polypeptide that is partially human and partially non-human, e.g., a non-human animal that expresses a chimeric human/non-human MHC I polypeptide.
  • the non-human animal only expresses the human or humanized MHC I polypeptide, e.g., chimeric human/non-human MHC I polypeptide, and does not express an endogenous non-human MHC I protein from an endogenous MHC I locus.
  • the chimeric human/non-human MHC I polypeptide comprises in its human portion a peptide binding domain of a human MHC I polypeptide.
  • the human portion of the chimeric polypeptide comprises an extracellular domain of a human MHC I.
  • the human portion of the chimeric polypeptide comprises an extracellular domain of an ⁇ chain of a human MHC I.
  • the human portion of the chimeric polypeptide comprises ⁇ l and ⁇ 2 domains of a human MHC I. In another embodiment, the human portion of the chimeric polypeptide comprises ⁇ l, ⁇ 2, and ⁇ 3 domains of a human MHC I.
  • the human or humanized MHC I polypeptide may be derived from a functional human HLA molecule encoded by any of HLA-A, HLA-B, or HLA-C loci. A list of commonly used HLA antigens is described in Shankarkumar et al. ((2004) The Human Leukocyte Antigen (HLA) System, Int. J. Hum. Genet. 4(2):91-103), incorporated herein by reference.
  • HLA dictionary 2008 a summary of HLA-A, -B, -C, - DRB1/3/4/5, and DQB1 alleles and their association with serologically defined HLA-A, -B, -C, - DR, and —DQ antigens, Tissue Antigens 73:95-170, and a recent update by Marsh et al. (2010) Nomenclature for factors of the HLA system, 2010, Tissue Antigens 75:291-455, both incorporated herein by reference.
  • the human or humanized MHC I polypeptide may be derived from any functional human HLA class I molecules described therein.
  • the human or humanized MHC I polypeptide is derived from human HLA-A.
  • the HLA-A polypeptide is an HLA-A2 polypeptide (e.g., and HLA-A2.1 polypeptide).
  • the human or humanized MHC I polypeptide is derived from human MHC I selected from HLA-B and HLA-C.
  • the human or humanized MHC I is derived from HLA-B, e.g., HLA-B27.
  • the non-human portion of the chimeric human/non-human MHC I polypeptide comprises transmembrane and/or cytoplasmic domains of the non-human MHC I polypeptide.
  • the non-human animal is a mouse, and the non-human MHC I polypeptide is selected from H-2K, H-2D, and H-2L.
  • the non-human MHC I polypeptide is H-2K, e.g., H-2Kb.
  • the non-human animal described herein may comprise in its genome a nucleotide sequence encoding a human or humanized MHC I polypeptide, e.g., chimeric human/non-human MHC I polypeptide, wherein the nucleotide sequence encoding such polypeptide is located at an endogenous non-human MHC I locus (e.g., H-2K locus).
  • an endogenous non-human MHC I locus e.g., H-2K locus.
  • this results in a replacement of an endogenous MHC I gene or a portion thereof with a nucleotide sequence encoding a human or humanized MHC I polypeptide, e.g., a chimeric gene encoding a chimeric human/non-human MHC I polypeptide described herein.
  • the replacement comprises a replacement of an endogenous nucleotide sequence encoding a non-human MHC I peptide binding domain or a non-human MHC I extracellular domain with a human nucleotide sequence (e.g., HLA-A2 nucleotide sequence) encoding the same.
  • the replacement does not comprise a replacement of an MHC I sequence encoding transmembrane and/or cytoplasmic domains of a non-human MHC I polypeptide (e.g., H-2K polypeptide).
  • the non-human animal contains chimeric human/non-human nucleotide sequence at an endogenous non-human MHC I locus, and expresses chimeric human/non-human MHC polypeptide from the endogenous non-human MHC I locus.
  • a chimeric human/non-human polypeptide may be such that it comprises a human or a non-human leader (signal) sequence.
  • the chimeric polypeptide comprises a non-human leader sequence of an endogenous MHC I protein.
  • the chimeric polypeptide comprises a leader sequence of a human MHC I protein, e.g., HLA-A2 protein (for instance, HLA-A2.1 leader sequence).
  • the nucleotide sequence encoding the chimeric MHC I polypeptide may be operably linked to a nucleotide sequence encoding a human MHC I leader sequence.
  • a chimeric human/non-human MHC I polypeptide may comprise in its human portion a complete or substantially complete extracellular domain of a human MHC I polypeptide.
  • the human portion may comprise at least 80%, preferably at least 85%, more preferably at least 90%, e.g., 95% or more of the amino acids encoding an extracellular domain of a human MHC I polypeptide (e.g., HLA-A2 polypeptide).
  • substantially complete extracellular domain of the human MHC I polypeptide lacks a human MHC I leader sequence.
  • the chimeric human/non-human MHC I polypeptide comprises a human MHC I leader sequence.
  • the chimeric MHC I polypeptide may be expressed under the control of endogenous non-human regulatory elements, e.g., rodent MHC I regulatory animals. Such arrangement will facilitate proper expression of the chimeric MHC I polypeptide in the non-human animal, e.g., during immune response in the non-human animal.
  • Non-limiting examples of chimeric human/non-human MHC I polypeptides, genetically modified non-human animals expressing the same, and methods of making the same are described in U.S. Patent No. 9,591,835, U.S. Patent No. 9,615,550, U.S. Patent No. 10,045,516, U.S. Patent No. 10,779,520, U.S. Patent No. 10,869,466, International Publication No. WO 2013/063346, and International Publication No. WO 2014/164640, each of which is herein incorporated by reference in its entirety.
  • the genetically modified rodent (e.g., mouse, rat, etc.) comprises in its germline a nucleotide sequence encoding a human or humanized MHC II complex, e.g., human or humanized MHC II ⁇ and/or ⁇ polypeptide(s).
  • a rodent e.g., a rat or a mouse, comprising in its genome, e.g., at an endogenous non-human MHC II locus, a nucleotide sequence encoding a human MHC II polypeptide.
  • a rodent e.g., a rat or a mouse, comprising in its genome, e.g., at an endogenous MHC II locus, a nucleotide sequence encoding a chimeric human/rodent MHC II polypeptide.
  • a rodent that comprises in its genome, e.g., at an endogenous non-human MHC II locus, a nucleotide sequence(s) encoding a human or a chimeric human/non-human MHC II complex.
  • the human portion of the MHC II ⁇ and ⁇ polypeptides described herein may be encoded by any of HLA-DP, -DQ, and –DR loci.
  • HLA-DP Human Leukocyte Antigen
  • -DQ Human Leukocyte Antigen
  • –DR loci A list of commonly used HLA antigens and alleles is described in Shankarkumar et al. ((2004) The Human Leukocyte Antigen (HLA) System, Int. J. Hum. Genet. 4(2):91-103), incorporated herein by reference.
  • Shankarkumar et al. also present a brief explanation of HLA nomenclature used in the art. Additional information regarding HLA nomenclature and various HLA alleles can be found in Holdsworth et al.
  • the HLA dictionary 2008 a summary of HLA-A, -B, -C, -DRB1/3/4/5, and DQB1 alleles and their association with serologically defined HLA-A, -B, -C, -DR, and –DQ antigens, Tissue Antigens 73:95-170, and a recent update by Marsh et al. (2010) Nomenclature for factors of the HLA system, 2010, Tissue Antigens 75:291-455, both incorporated herein by reference.
  • the human or humanized MHC II polypeptide may be derived from any functional human HLA molecules described therein.
  • the human portions of the humanized MHC II complex described herein are derived from human HLA-DR, e.g., HLA-DR4 or HLA-DR2.
  • HLA-DR ⁇ chains are monomorphic, e.g., the ⁇ chain of HLA-DR complex is encoded by HLA-DRA gene (e.g., HLA-DR ⁇ 1*01 gene).
  • HLA-DR ⁇ chain is polymorphic.
  • HLA-DR4 comprises an ⁇ chain encoded by HLA-DRA gene and a ⁇ chain encoded by HLA- DRB1 gene (e.g., HLA-DR ⁇ 1*04 gene).
  • the HLA-DRB allele is HLA-DR ⁇ 1*04, e.g., HLA- DR ⁇ 1*04:01:01. In another embodiment, the HLA-DRB allele is HLA- DR ⁇ 1*02, e.g., HLA- DR ⁇ 1*1501. [0073] In another specific embodiment, the human portions of the humanized MHC II complex described herein are derived from human HLA-DQ, e.g., HLA-DQ2 and HLA-DQ8. HLA-DQ2 comprises an ⁇ chain encoded by HLA-DQA gene (e.g., HLA-DQ ⁇ 1*05 gene).
  • HLA-DQ ⁇ 1*05 gene is HLA-DQ ⁇ 1*0501.
  • HLA-DQ2 also comprises a ⁇ chain encoded by HLA-DQB gene (e.g., HLA-DQ ⁇ 1*02 gene).
  • HLA-DQ8 comprises an ⁇ chain encoded by HLA-DQA gene (e.g., HLA-DQ ⁇ 1*0301 gene).
  • HLA-DQ8 also comprises a ⁇ chain encoded by HLA-DQB gene (e.g., HLA-DQ ⁇ 1*0302 gene).
  • HLA-DQ2.5 and HLA-DQ8 alleles are known to be associated with such diseases as Celiac disease and type I diabetes.
  • the replacement comprises a replacement of an endogenous nucleotide sequence encoding an MHC II ⁇ and ⁇ polypeptides with a nucleotide sequence encoding a chimeric human/non-human MHC ⁇ polypeptide and a chimeric human/non-human MHC ⁇ polypeptide.
  • the replacement comprises replacing nucleotide sequences representing one or more (e.g., two) endogenous MHC II genes.
  • the rodent contains a chimeric human/non-human nucleotide sequence at an endogenous MHC II locus, and expresses a chimeric human/non-human MHC II protein from the endogenous non- human locus.
  • a rodent e.g., a mouse or rat
  • a rodent that expresses a functional chimeric MHC II protein from a chimeric MHC II locus as described herein displays the chimeric protein on a cell surface.
  • the rodent expresses the chimeric MHC II protein on a cell surface in a cellular distribution that is the same as observed in a human.
  • the cell displays a peptide fragment (antigen fragment) bound to an extracellular portion (e.g., human HLA -DQ2 extracellular portion) of the chimeric MHC II protein.
  • a cell displaying the chimeric MHC II protein e.g., HLA- DQ8/H-2A protein
  • APC antigen-presenting cell
  • the peptide fragment presented by the chimeric protein is derived from a tumor.
  • the peptide fragment presented by the chimeric MHC II protein is derived from a pathogen, e.g., a bacterium, a virus, or a parasite.
  • a pathogen e.g., a bacterium, a virus, or a parasite.
  • Non-limiting examples of chimeric human/non-human MHC II polypeptides, genetically modified non-human animals expressing the same, and methods of making the same are described in U.S. Patent No. 8,847,005, U.S. Patent No. 9,043,996, U.S. Patent No. 9,585,373, U.S. Patent No. 9,700,025, U.S. Patent No. 10,219,493, U.S. Patent No. 10,986,822, U.S. Patent No. 11,219,195, International Publication No.
  • the human or humanized MHC e.g., classical HLA, molecule described herein may interact with other proteins on the surface of the same cell or a second cell.
  • the human or humanized MHC interacts with endogenous rodent proteins on the surface of said cell.
  • the human or humanized MHC molecule may also interact with human or humanized proteins on the surface of the same cell or a second cell.
  • the second cell is a T cell, and the human or humanized MHC molecule interacts with T cell receptor (TCR) and/or its co-receptor CD4.
  • TCR T cell receptor
  • the T cell is a human T cell.
  • the TCR is a human or humanized TCR.
  • the genetically modified rodent exhibits one or more symptoms of a disease associated with the human or humanized MHC, e.g., classical HLA, molecule.
  • the genetically modified rodent exhibits one or more symptoms of a disease associated with the antigen presented by the human or humanized MHC.
  • the genetically modified rodent exhibits one or more symptoms of a disease associated with the combination of the human or humanized MHC, e.g., classical HLA, molecule and the antigen.
  • the genetically modified rodent comprises a nucleotide sequence, e.g., a nucleic acid, encoding at least an antigen presenting portion of an MHC, e.g., HLA, molecule that is associated with a disease as set forth in Table 1 below.
  • the antigen presented by the MHC, e.g., HLA, molecule comprises an antigen, or a portion thereof, that is associated with the disease as set forth in Table 1 below.
  • the genetically modified rodent exhibits one or more characteristics of the disease listed in Table 1 below. Table 1. Disease associated HLA molecules and alleles.
  • the genetically modified rodent comprises a nucleotide sequence, e.g., a nucleic acid, encoding at least an antigen presenting portion of an HLA-DQ2.5 molecule.
  • the antigen is gliadin, or portion thereof.
  • the antigen presenting portion of an HLA-DQ2.5 molecule presents a peptide derived from gliadin.
  • the gliadin selected from the group consisting of: an ⁇ gliadin, a ⁇ gliadin, and an ⁇ gliadin.
  • the gliadin is an ⁇ 1, ⁇ 2, ⁇ 1 or ⁇ 2 gliadin.
  • the gliadin is an ⁇ 1 gliadin.
  • the genetically modified rodent exhibits one or more characteristics of celiac disease.
  • the genetically modified rodent comprises an activated effector T cell that specifically binds gliadin, or a portion thereof, presented in the context of the antigen presenting portion of HLA-DQ2.5.
  • the activated effector T cell expresses an activation-induced marker (AIM).
  • AIM is selected from the group consisting of Ki67, IFNG, GZMB, 4-1BB, HLA-DR, ICOS, PD1, CD39, and CCL5.
  • the activated effector T cell is found in the blood, spleen and/or small intestine of the genetically modified rodent.
  • Genetically Modified T cells [0091]
  • the genetically modified rodent as described herein further comprises, in its periphery, a human T cell, e.g., a human T cell that has been genetically modified, e.g., an engineered human T cell.
  • Human T cells as described herein may be prepared using various methods known in the art.
  • human T cells are enriched from healthy donor peripheral blood mononuclear cells (PBMCs).
  • PBMCs may be isolated from a donor, e.g., human subject, via methods known in the art. For example, whole blood samples may be subject to density gradient centrifugation and the PBMC fraction isolated therefrom.
  • T cells can be further enriched via various methods known in the art. For example, T cells may be separated from non-T cells in a PBMC sample, e.g., B cells, monocytes, dendritic cells, using immunomagnetic negative selection.
  • isolated human T cells e.g., engineered human T cells
  • a rodent e.g., via intravenous injection.
  • the human T cell is genetically modified to express a recombinant nucleic acid that encodes (at least) a recombinant human TCR variable domain.
  • TCR variable domain encompasses a variable domain of a TCR ⁇ chain, e.g., TCR ⁇ variable domain, a variable domain of a TCR ⁇ chain, e.g., a TCR ⁇ variable domain, or a variable domain of a TCR comprising cognate TCR ⁇ and TCR ⁇ chains, e.g., both a TCR ⁇ variable domain and a TCR ⁇ variable domain.
  • the human T cell is genetically modified to express a recombinant nucleic acid that encodes (at least) a recombinant human TCR ⁇ variable domain.
  • the human T cell is genetically modified to express a recombinant nucleic acid that encodes (at least) a recombinant human TCR ⁇ variable domain. In some embodiments, the human T cell is genetically modified to express a recombinant nucleic acid that encodes (at least) a recombinant human TCR ⁇ variable domain and (at least) a recombinant human TCR ⁇ variable domain. In some embodiments, a human T cell as described herein expresses a recombinant nucleic acid that encodes a recombinant human TCR, i.e., variable and constant domains of the TCR ⁇ and ⁇ chains.
  • the human T cell expresses the recombinant human TCR variable domain and/or human TCR on its cell surface.
  • the recombinant human TCR variable domain and/or human TCR binds an antigen presented in the context of the antigen presenting portion of a human or humanized MHC as described herein.
  • the recombinant human TCR variable domains and/or TCR ⁇ and ⁇ chains are fused to a linker sequence.
  • linker sequences are a furin-cleavable linker and/or a self- cleavable 2A peptide (P2A, T2A, E2A, F2A).
  • the recombinant nucleic acid that encodes the recombinant human TCR variable domain is operably linked to a non-human promoter.
  • the non-human promoter controls expression of the recombinant human TCR variable domain.
  • Non- limiting examples of non-human promoters include EF1 ⁇ promoter, spleen focus-forming virus (SFFV) promoter, etc.
  • the recombinant nucleic acid that encodes the recombinant human TCR variable domain is operably linked to a non-human regulatory element. In some embodiments, the non-human regulatory element enhances expression of the recombinant human TCR variable domain.
  • the engineered T cell comprises a viral nucleic acid.
  • the viral nucleic acid encodes a 2A peptide.
  • Non-limiting examples of 2A peptides include a T2A peptide, a P2A peptide, a F2A peptide, etc.
  • the T cell comprises an adeno-associated viral (AAV) nucleic acid.
  • the AAV nucleic acid is an AAV inverted terminal repeat (ITR).
  • the TCR of the engineered human T cell is an HLA-restricted, e.g., HLA-DQ2.5-restricted, TCR.
  • the TCR is an antigen-specific, e.g., gliadin-specific, e.g., ⁇ 1 gliadin-specific, TCR.
  • the TCR is an HLA- restricted antigen-specific, e.g., HLA-DQ2.5-restricted ⁇ 1-gliadin-specific, TCR.
  • the recombinant human TCR variable domain comprises a TCR ⁇ variable domain encoded by a TRAV9-2 gene segment.
  • the TCR ⁇ variable domain comprises a complementary determining region (CDR) 3 that comprises an amino acid sequence of ALSDHYSSGSARQLT (SEQ ID NO: 10).
  • the TCR ⁇ variable domain is encoded by the TRAV9-2 gene segment and comprises a CDR3 that comprises an amino acid sequence of ALSDHYSSGSARQLT (SEQ ID NO: 10).
  • the recombinant human TCR variable domain comprises a TCR ⁇ variable domain encoded by a TRBV7-2 gene segment.
  • the TCR ⁇ variable domain comprises a CDR3 that comprises an amino acid sequence of ASSTAVLAGGPQY (SEQ ID NO: 14).
  • the TCR ⁇ variable domain is encoded by the TRBV7-2 gene segment and comprises a CDR3 that comprises an amino acid sequence of ASSTAVLAGGPQY (SEQ ID NO: 14).
  • the recombinant human TCR variable domain comprises a TCR ⁇ variable domain comprising a CDR1, CDR2 and CDR3 comprising the amino acid sequences set forth in SEQ ID NO: 8, SEQ ID NO: 9, and SEQ ID NO: 10, respectively.
  • the recombinant human TCR variable domain comprises a TCR ⁇ variable domain comprising a CDR1, CDR2 and CDR3 comprising the amino acid sequences set forth in SEQ ID NO: 12, SEQ ID NO: 13, and SEQ ID NO: 14, respectively.
  • the recombinant human TCR variable domain comprises a TCR ⁇ variable domain comprising the amino acid sequence as set forth in SEQ ID NO: 11.
  • the recombinant human TCR variable domain comprises a TCR ⁇ variable domain comprising the amino acid sequence as set forth in SEQ ID NO: 15. In one embodiment, the recombinant human TCR variable domain comprises a TCR ⁇ variable domain comprising the amino acid sequence as set forth in SEQ ID NO: 11 and a TCR ⁇ variable domain comprising the amino acid sequence as set forth in SEQ ID NO: 15. [00100] In some embodiments, the recombinant human TCR variable domain comprises a TCR ⁇ variable domain encoded by a TRAV26-1 gene segment. In some embodiments, the TCR ⁇ variable domain comprises a CDR3 that comprises an amino acid sequence of IVTNNNDMR (SEQ ID NO: 16).
  • the recombinant TCR variable domain comprises a TCR ⁇ variable domain comprising a CDR3 comprising the amino acid sequence of IVTNNNDMR (SEQ ID NO: 16) and a TCR ⁇ variable domain comprising a CDR3 comprising the amino acid sequence of ASSIRSTDTQY (SEQ ID NO: 17).
  • Genetically Modifying T Cells [00101] Various methods, systems, and compositions are provided herein to allow for introduction of a nucleic acid into a cell, e.g., genetically modifying human T cells.
  • nucleic acids include, for example, vector delivery, particle-mediated delivery, exosome-mediated delivery, lipid-nanoparticle (LNP)- mediated delivery, cell-penetrating-peptide-mediated delivery, etc.
  • LNP lipid-nanoparticle
  • electroporation is used.
  • Introduction of nucleic acids e.g., a recombinant nucleic acid that encodes the recombinant human TCR variable domain, genome editing agents, etc.
  • virus-mediated delivery such as AAV-mediated delivery or lentivirus-mediated delivery.
  • viruses/viral vectors include retroviruses, adenoviruses, vaccinia viruses, poxviruses, and herpes simplex viruses.
  • the viruses can integrate into the T cell genome or alternatively do not integrate into the T cell genome.
  • the viruses can be replication-competent or can be replication-defective (e.g., defective in one or more genes necessary for additional rounds of virion replication and/or packaging).
  • Viruses can cause transient expression, long- lasting expression (e.g., at least 1 week, 2 weeks, 1 month, 2 months, or 3 months), or permanent expression.
  • the nucleic acid construct comprising a sequence encoding a recombinant human TCR variable domain(s) is introduced via lentivirus-mediated delivery.
  • Such methods include introducing into the T cell one or more genome editing agents, thereby producing a genetically modified T cell, e.g., an engineered T cell.
  • the one or more genome editing agents comprises a nuclease agent or one or more nucleic acids encoding the nuclease agent.
  • the nuclease agent e.g., Cas9 protein
  • can cleave a nuclease target sequence e.g., a guide RNA target sequence
  • the nuclease agent can be a zinc finger nuclease (ZFN), a Transcription Activator-Like Effector Nuclease (TALEN), or a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-associated (Cas) protein and a guide RNA (gRNA) (e.g., a Cas9 protein and a guide RNA).
  • ZFN zinc finger nuclease
  • TALEN Transcription Activator-Like Effector Nuclease
  • CRISPR Clustered Regularly Interspaced Short Palindromic Repeats
  • Cas Cas9 protein and a guide RNA
  • the nuclease agent target sequence includes an endogenous TCR ⁇ chain sequence and/or TCR ⁇ chain sequence, and the nuclease agent cleavage leads to the knockout of an endogenous TCR ⁇ chain gene and/or TCR ⁇ chain gene.
  • cleavage by the nuclease agent can result in disruption of an endogenous TCR ⁇ and/or endogenous TCR ⁇ gene so that a functional endogenous TCR ⁇ and/or endogenous TCR beta ⁇ is not produced.
  • Methods of genetically modifying human T cells described herein also include introducing a nucleic acid construct comprising a sequence encoding a recombinant human TCR variable domain (or a nucleic acid construct comprising sequence(s) encoding recombinant human TCR ⁇ variable domain and/or a TCR ⁇ variable domain).
  • the nuclease agent (or nucleic acid encoding the nuclease agent or one or more nucleic acids encoding the nuclease agent) is introduced simultaneously with the nucleic acid construct (e.g., via electroporation). In some embodiments, the nuclease agent (or nucleic acid encoding the nuclease agent or one or more nucleic acids encoding the nuclease agent) is introduced before the nucleic acid construct (e.g., nuclease agent administered by electroporation, followed by infection with recombinant AAV/lentiviral nucleic acid construct).
  • a Cas protein (or nucleic acid encoding a Cas protein) and a guide RNA (or DNA encoding a guide RNA) can be introduced simultaneously or sequentially in any combination.
  • a Cas protein (or nucleic acid encoding a Cas protein) can be introduced into a cell or subject before introduction of a guide RNA (or DNA encoding the guide RNA), simultaneously with a guide RNA (or DNA encoding the guide RNA), or after introduction of a guide RNA (or DNA encoding the guide RNA).
  • two or more of the components can be introduced into the cell or subject by the same delivery method or different delivery methods.
  • a guide RNA can be introduced into the cell in the form of an RNA molecule (e.g., in vitro transcribed RNA molecule) or in the form of a DNA molecule encoding the guide RNA.
  • protein components such as Cas proteins, ZFNs, or TALENs can be introduced into the cell in the form of DNA, RNA, or protein.
  • a Cas protein and a guide RNA can be introduced together as a ribonucleoprotein (RNP) complex.
  • RNP ribonucleoprotein
  • a guide RNA and a Cas protein can both be introduced in the form of RNA (i.e., guide RNA and an mRNA molecule encoding the Cas protein).
  • the guide RNA and the mRNA molecule encoding the Cas protein can be delivered via LNP-mediated delivery.
  • a guide RNA and a Cas protein can both be introduced in the form of DNA (e.g., in one or more lentiviral or AAV vectors encoding the guide RNA and Cas protein).
  • DNA e.g., in one or more lentiviral or AAV vectors encoding the guide RNA and Cas protein.
  • the nucleic acid construct comprising a sequence encoding the recombinant human TCR variable domain (e.g., a human TCR ⁇ variable domain and/or a human TCR ⁇ variable domain) is inserted at a locus that is not the endogenous TCR locus.
  • the nucleic acid construct comprising a sequence encoding the recombinant human TCR variable domain (e.g., a human TCR ⁇ variable domain and/or a human TCR ⁇ variable domain) is randomly integrated into the genome of a T cell.
  • the nucleic acid construct comprising a sequence encoding the recombinant human TCR variable domain is episomal.
  • an antigen is introduced into a genetically modified non- human animal as described herein that has been engrafted with genetically modified human T cells, e.g., engineered human T cells, as described herein.
  • the genetically modified human T cell expresses a TCR comprising a TCR variable domain(s) that is specific for the antigen, such that upon introducing the antigen the genetically modified human T cell exhibits an effector memory phenotype.
  • Non-limiting examples of an effector memory phenotype include CD45RO + , CD62L- T cells and CCR7 lo , CD45RA- T cells.
  • the human T cell is found in the blood, spleen, or small intestine.
  • the human T cell expresses an AIM, e.g., Ki67, IFNG, GZMB, 4-1BB, HLA-DR, ICOS, PD1, CD39, CCL5, etc.
  • a genetically modified rodent e.g., a mouse or rat, that expresses at least an antigen presenting portion of a classical HLA and that comprises a genetically engineered human T cell, as described herein may further comprise one or more additional genetic modifications.
  • the one or more genetic modifications may comprise modifications that enhance the development (e.g., the proper migration, homing, engraftment, survival, proliferation, production and/or differentiation) and/or proper function (e.g., phenotypic responses, such as immune responses) of transplanted human cells in the genetically modified rodent.
  • the genetically modified rodents as described herein further comprise genetic modifications that enhance the adoptive transfer of human T cells.
  • the one or more genetic modifications that enhance the adoptive transfer of human cell may comprise knockout mutations that provide for an immunodeficient background and/or humanizations in which an exogenous nucleic acid sequence is inserted into the genome of the rodent to form a humanized gene that encodes a human or humanized polypeptide that promotes the development and/or function of transplanted human cells.
  • the human or humanized polypeptides may act on (e.g., bind) human biomolecules (e.g., receptors or ligands) for which the polypeptide’s endogenous rodent homolog is not cross-reactive, is insufficiently cross-reactive, and/or is expressed at non-optimal concentrations.
  • a humanized gene may be designed to encode a human or humanized polypeptide which exhibits wildtype human function, such as reactivity with wildtype human biomolecules.
  • human or humanized receptor polypeptides may exhibit wildtype human receptor function (binding of human ligands and activation in response thereto) and human or humanized ligand polypeptides may exhibit wildtype human ligand function (binding and activation of human receptors).
  • the exogenous nucleic acids forming these humanized genes may be randomly integrated into the rodent genome or may be inserted in a targeted manner into the endogenous locus of the homologous rodent gene that encodes the homologous rodent polypeptide, either at one or both alleles.
  • the exogenous nucleic acid sequence may replace some or all of the genomic sequence at the endogenous locus, such as a homologous endogenous nucleic acid sequence (e.g., the coding region or a portion thereof).
  • the humanized gene may effectively replace the endogenous gene such that the endogenous polypeptide normally encoded at the endogenous gene is effectively replaced by the human or humanized polypeptide.
  • the sequence encoding a human or humanized polypeptide may be operably linked to a promoter, such as an endogenous promoter for the rodent’s homologous gene (e.g., operably linked to the native promoter at the endogenous locus for the homologous gene within the genome).
  • the genetically modified rodents as described herein do not comprise, in their periphery, mature rodent B cells, mature rodent T cells, and/or rodent NK cells.
  • Various strategies for developing immune-compromised or immune-deficient rodents e.g., mice and rats, are well known in the art.
  • NOG NOD Shi-SCID yc null
  • NSG NOD ltz-SCID yc -/-
  • Balb/c Rag -/- yc -/- mice have all been well characterized. See, e.g., Drake, et al. Cell Mol Immunol.
  • a rodent e.g., mouse
  • a rodent includes at least one null allele for the Il2rg gene (“interleukin 2 receptor, gamma”, also known as the common gamma chain, or ⁇ C, wherein the coding sequence for the mouse gene may be found at Genbank Accession No. NM 013563.3, Gene symbol: Il2rg).
  • the rodent e.g., mouse
  • the rodent includes two null alleles for Il2rg.
  • a rodent e.g., mouse
  • the (endogenous) Rag gene comprises an (endogenous) Rag2 gene, wherein the coding sequence for the mouse gene may be found, for example, at GenBank Accession No. NM_009020.4.
  • a rodent (e.g., mouse) provided herein comprises two null alleles for a Rag gene, e.g., is homozygous for the knockout mutation of the (endogenous) Rag, e.g., (endogenous) Rag2, gene.
  • the rodent e.g., mouse
  • the rodent comprises two null alleles for an Il2r gene, e.g., is homozygous for the knockout mutation of the (endogenous) Il2r, e.g., (endogenous) Il2r ⁇ , gene.
  • the rodent e.g., mouse
  • the rodent e.g., mouse
  • the rodent comprises a null allele for both Rag2 and Il2r ⁇ , i.e., it is Rag2 -/- Il2r ⁇ -/- (or Rag2 -/- Il2r ⁇ Y/- where the Il2r ⁇ gene is located on the X chromosome as in mouse).
  • a Rag2 null Il2r ⁇ null background may be abbreviated in certain models as “RG”.
  • Interleukin 15 [00114] Interleukin 15 (IL-15) [00114] IL-15 (NCBI Gene IDs: 3600 (homo sapiens), Gene symbol: IL15; 16168 (mus musculus), Gene symbol: Il15) is a pleiotropic cytokine required for NK cell development and function and T cell homeostasis, being particularly important for the memory CD8+ T cell compartment. IL-15 is produced primarily by dendritic cells and macrophages and is trans- presented via IL-15/IL-15R complex to NK cells and T cells.
  • cytokine It is a pro-inflammatory cytokine at the apex of a signaling cascade that induces production of other cytokines, recruits and activates T-cells and other inflammatory cells, promotes development and survival of NK cells, and promotes angiogenesis.
  • IL-15 derived from endothelial cells stimulates trans-endothelial migration of T cells and recruitment to inflammatory cites.
  • Expression of human or humanized IL-15 (hIL-15), particularly at physiological concentrations, may be particularly useful for maintaining xenografts, including lymphocyte tumors, and the development of NK cells in rodents.
  • a rodent described herein may comprise an hIL-15 gene and/or otherwise express an hIL-15 polypeptide.
  • the hIL-15 polypeptide may be a full-length human polypeptide (e.g., wildtype human polypeptide) or comprise a functional fragment thereof. According to certain aspects of the disclosure, the hIL-15 polypeptide may be a fully human IL-15 polypeptide. According to certain aspects of the disclosure, the mature hIL- 15 polypeptide (lacking a signal peptide and the removed proprotein sequence) may be fully human. According to certain aspects of the disclosure, the hIL15 gene may comprise an endogenous rodent Il155’ UTR. According to certain aspects of the disclosure, the hIL15 gene may comprise a human IL153’ UTR.
  • the hIL15 gene may comprise exons 1 and 2 of an endogenous rodent Il15 gene (e.g., the native exons within the endogenous rodent Il15 locus of the genome of the genetically modified rodent).
  • the genetically modified rodent may be heterozygous or homozygous for the hIL15 gene.
  • the genetically modified rodent may be modified in such a manner that it does not express any wild-type rodent IL-15 polypeptide.
  • the genetically modified rodent is homozygous for a replacement of the endogenous Il15 gene with the hIL15 gene, i.e., such that rodent does not comprise an endogenous Il15 gene or express a wild-type rodent IL-15 polypeptide.
  • rodents that have been or are to be engrafted, e.g., administered (genetically modified) human T cells, in accordance with technologies described herein, wherein the rodent is genetically modified to further express a human IL-15 protein encoded by a nucleic acid operably linked to an Il15 promoter.
  • human IL-15 protein means a protein that is a wild-type (or native) human IL-15 protein or a variant of a wild-type (or native) human IL-15 protein, which retains one or more signaling functions of a wild-type (or native) human IL-15 protein, e.g., which allows for stimulation of (or signaling via) the human IL-15 receptor, and/or which is capable of binding to the human IL-15 receptor alpha subunit of the human IL-15 receptor, and/or which is capable of binding to IL-2R beta/IL-15R beta and the common ⁇ -chain ( ⁇ c).
  • ⁇ c common ⁇ -chain
  • human IL-15 protein also encompassed by the term “human IL-15 protein” are fragments of a wild-type human IL-15 protein (or variants thereof), which retain one or more signaling functions of a wild-type human IL-15 protein, e.g., a fragment of a human IL-15 protein, which allows for stimulation of (or signaling via) the human IL-15 receptor, and/or which is capable of binding to the human IL-15 receptor alpha subunit of the human IL-15 receptor, and/or which is capable of binding to IL-2R beta/IL-15R beta and the common ⁇ -chain ( ⁇ c).
  • a wild-type human IL-15 protein e.g., a fragment of a human IL-15 protein, which allows for stimulation of (or signaling via) the human IL-15 receptor, and/or which is capable of binding to the human IL-15 receptor alpha subunit of the human IL-15 receptor, and/or which is capable of binding to IL-2R beta/IL-15R beta and the common ⁇ -chain (
  • human IL-15 protein also encompasses fusion proteins, i.e., chimeric proteins, which include one or more fragments of a wild-type human IL-15 protein (or a variant thereof) and which retain one or more signaling functions of a wild-type human IL-15 protein, e.g., as described above.
  • a fusion protein which includes one or more fragments of a wild-type human IL-15 protein (or a variant thereof) may also be referred to herein as a humanized IL-15 protein.
  • IL-15 (also known as “Interleukin 15”) is a cytokine that stimulates the proliferation of T lymphocytes.
  • Polypeptide sequence for wild-type human IL-15 and the nucleic acid sequence that encodes wild-type human IL-15 may be found at Genbank Accession Nos. NP_000576.1 and NM_000585.5 (isoform 1 and transcript variant 3), NP 751915.1 and NM_172175.3 (isoform 2 and transcript variant 2).
  • the genomic locus encoding the wild-type human IL-15 protein may be found in the human genome at Chromosome 4; NC 000004.12 (141636583-141733987) or NG_029605.2 (4988-102392).
  • the nucleic acid sequence includes exons 5-8 of the human IL15 genomic locus (i.e., coding exons 3-6).
  • the nucleic acid sequence that encodes a human IL-15 protein is operably linked to one or more regulatory sequences of an Il15 gene, e.g., a regulatory sequence of an Il15 gene of the rodent.
  • the humanized IL-15 rodent e.g., mouse
  • the humanized IL-15 rodent is generated by the random integration, or insertion, of a human nucleic acid sequence encoding a human IL-15 protein (including fragments as described above), i.e., a “human IL-15 nucleic acid sequence”, or “human IL-15 sequence”, into the genome of the rodent.
  • a human IL-15 nucleic acid sequence e.g., mouse
  • the humanized IL-15 rodent is generated by the targeted integration, or insertion, of human IL-15 nucleic acid sequence into the genome of the rodent, by, for example, homologous recombination.
  • a polynucleotide is inserted into the host genome at a target locus while simultaneously removing host genomic material, e.g., 50 base pairs (bp) or more, 100 bp or more, 200 bp or more, 500 bp or more, 1 kB or more, 2 kB or more, 5 kB or more, 10 kB or more, 15 kB or more, 20 kB or more, or 50 kB or more of genomic material, from the target locus.
  • host genomic material e.g., 50 base pairs (bp) or more, 100 bp or more, 200 bp or more, 500 bp or more, 1 kB or more, 2 kB or more, 5 kB or more, 10 kB or more, 15 kB or more, 20 kB or more, or 50 kB or more of genomic material, from the target locus.
  • human IL15 nucleic acid sequence may replace some or all of the mouse sequence, e.g., exons and/or introns, at the Il15 locus.
  • a human IL15 nucleic acid sequence is integrated into the mouse Il15 locus such that expression of the human IL15 sequence is regulated by the native, or endogenous, regulatory sequences at the mouse Il15 locus.
  • the regulatory sequence(s) to which the nucleic acid sequence encoding a human IL-15 protein is operably linked are the native Il15 regulatory sequences at the mouse Il15 locus.
  • the integration of a human IL15 sequence does not affect the transcription of the gene into which the human IL15 sequence has integrated. For example, if the human IL15 sequence integrates into a coding sequence as an intein, or the human IL15 sequence includes a 2A peptide, the human IL15 sequence will be transcribed and translated simultaneously with the gene into which the human IL15 sequence has integrated. In other instances, the integration of the human IL15 sequence interrupts the transcription of the gene into which the human IL15 sequence has integrated.
  • the humanized IL-15 rodent may be heterozygous for the nucleic acid sequence encoding human IL-15, i.e., the humanized IL-15 rodent includes one null allele for the rodent Il15 (the allele including the nucleic acid sequence) and one endogenous Il15 allele (wild-type or otherwise). In other instances, the humanized IL-15 rodent includes two copies of the nucleic acid sequence encoding a human IL-15 protein.
  • the rodent e.g., mouse
  • the rodent may be homozygous for the nucleic acid sequence, i.e., both alleles for a locus in the diploid genome will include the nucleic acid sequence, i.e., the humanized IL-15 rodent includes two null alleles for the rodent Il15 (the allele including the nucleic acid sequence).
  • the humanized IL-15 rodent includes two null alleles for the rodent Il15 (the allele including the nucleic acid sequence).
  • Human IL-15 polypeptides, loci encoding human IL-15 polypeptides and rodents expressing human IL-15 polypeptides are described in WO 2016/168212, which is herein incorporated by reference in its entirety.
  • SIRP ⁇ Signal regulatory protein ⁇
  • SIRP ⁇ or SIRPa NCBI Gene IDs: 140885 (homo sapiens), Gene symbol: SIRPA; 19261 (mus musculus), Gene symbol: Sirpa
  • CD47 is a transmembrane protein that binds to SIRP ⁇ on macrophages to negatively regulate phagocytosis.
  • hSIRP ⁇ humanized SIRP ⁇
  • a rodent described herein may comprise an hSIRPA gene and/or otherwise express an hSIRP ⁇ polypeptide.
  • the hSIRP ⁇ polypeptide may be a full-length human polypeptide (e.g., wildtype human polypeptide) or comprise a functional fragment thereof.
  • the hSIRP ⁇ polypeptide may be a fully human SIRP ⁇ polypeptide.
  • the hSIRP ⁇ polypeptide comprises a human extracellular domain (e.g., the extracellular portion of a human SIRP ⁇ protein).
  • the chimeric polypeptide may be a rodent SIRP ⁇ polypeptide having its extracellular domain, or a substantial portion thereof, replaced with a human SIRP ⁇ extracellular domain.
  • the hSIRPA gene is at an endogenous sirpa locus.
  • the hSIRPA gene replaces an endogenous sirpa gene.
  • the rodent e.g., a mouse
  • the hSIRPA gene may comprise exons 1, 5, 6, 7, and 8 of an endogenous rodent sirpa gene (e.g., the native exons within the endogenous rodent sirpa locus of the genome of the genetically modified rodent).
  • the genetically modified rodent may be heterozygous or homozygous for the hSIRPA gene.
  • the genetically modified rodent may be modified in such a manner that it does not express any wild-type rodent SIRP ⁇ polypeptide.
  • rodents are provided that have been or are to be engrafted with human cells according to methods described herein, wherein the genetically modified rodents provided herein further express a human or humanized SIRP ⁇ protein encoded by a nucleic acid operably linked to a sirpa promoter.
  • SIRP ⁇ (also referred to as CD172A, SHPS1, P84, MYD-1, BIT and PTPNS1) is expressed on immune cells of the myeloid lineage and functions as an inhibitory receptor via an immunoreceptor tyrosine-based inhibitory motif (ITIM). SIRP ⁇ expression has also been observed on neurons. Reported ligands for SIRP ⁇ include, most notably, CD47, but also include surfactant proteins A and D. The role of SIRP ⁇ , in particular, has been investigated in respect of its inhibitory role in the phagocytosis of host cells by macrophages. For example, CD47 binding to SIRP ⁇ on macrophages, triggers inhibitory signals that negatively regulates phagocytosis.
  • ITIM immunoreceptor tyrosine-based inhibitory motif
  • SIRP ⁇ has been shown to improve cell engraftment in immunodeficient mice (Strowig et al. Proc Natl Acad Sci USA 2011; 108: 13218-13223).
  • Polypeptide sequences for wild-type human SIRP ⁇ and the nucleic acid sequences that encode wild-type human SIRP ⁇ may be found at Genbank Accession Nos.
  • NP_001035111.1 and NM_001040022.1 isoform 1 and transcript variant 1
  • NP_001035112.1 and NM_001040023.2 isoform 1 and transcript variant 2
  • NP_001317657.1 and NM_001330728.1 isoform 2 and transcript variant 4
  • NP_542970.1 and NM_080792.3 isoform 1 and transcript variant 3
  • the SIRP ⁇ gene is conserved in at least chimpanzee, Rhesus monkey, dog, cow, mouse, rat, and chicken.
  • the genomic locus encoding the wild-type human SIRP ⁇ protein may be found in the human genome at Chromosome 20; NC_000020.11 (1894167-1940592).
  • human SIRP ⁇ protein is encoded by exons 2 through 9 at this locus.
  • a nucleic acid sequence including coding sequence for human SIRP ⁇ includes one or more of exons 2-9 of the human SIRPA gene.
  • the nucleic acid sequence also includes aspects of the genomic locus of the human SIRPA, e.g., introns, 3' and/or 5' untranslated sequence (UTRs).
  • the nucleic acid sequence includes whole regions of the human SIRPA genomic locus.
  • the nucleic acid sequence includes exons 2-4 of the human SIRPA genomic locus.
  • mouse SIRP ⁇ cDNA, mouse SIRP ⁇ protein, human SIRP ⁇ cDNA, and human SIRP ⁇ protein sequences are described in U.S. Pat. No. 11,019,810, which is herein incorporated by reference in its entirety.
  • a representative humanized SIRP ⁇ protein is set forth in SEQ ID NO: 18.
  • the rodents provided herein express humanized SIRP ⁇ proteins on the surface of immune cells (e.g., myeloid cells) of the rodents resulting from a genetic modification of an endogenous locus of the rodent that encodes a SIRP ⁇ protein. Suitable examples described herein include rodents, in particular, mice.
  • an endogenous sirpa gene is altered, wherein a portion of the endogenous sirpa gene is replaced with a heterologous sequence (e.g., a human SIRPA sequence in whole or in part). In some embodiments, all or substantially all of an endogenous sirpa gene is replaced with a heterologous gene (e.g., a human SIRPA gene). In some embodiments, a portion of a heterologous SIRPA gene is inserted into an endogenous non-human sirpa gene at an endogenous sirpa locus. In some embodiments, the heterologous gene is a human gene.
  • a humanized SIRPA gene includes a SIRPA gene that has a nucleotide coding sequence (e.g., a cDNA sequence) at least 50% (e.g., 50%, 55%, 60%0, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identical to nucleotides 352-1114 that appear in a human SIRPA cDNA sequence.
  • a nucleotide coding sequence e.g., a cDNA sequence
  • a humanized SIRP ⁇ a protein produced by a rodent of the present disclosure has an extracellular portion having a sequence that is at least 50% (e.g., 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identical to amino acid residues 28-362 that appear in a human SIRP ⁇ protein.
  • the modification does not affect the assembly of a functional receptor on the plasma and maintains normal effector functions via binding and subsequent signal transduction through the cytoplasmic portion of the receptor which is unaffected by the modification.
  • rodents that comprise humanized SIRPA genes.
  • such rodents comprise a humanized SIRPA gene operably linked to an endogenous sirpa promoter.
  • rodents express a humanized SIRPA protein from an endogenous locus, wherein the humanized SIRPA protein comprises amino acid residues 28-362 of a human SIRP ⁇ protein.
  • CD47 (NCBI Gene IDs: 961 (homo sapiens), Gene symbol: CD47; 16423 (mus musculus), Gene symbol: Cd47) is involved in bidirectional signaling that regulates a variety of cell-to-cell responses such as, for example, inhibition of phagocytosis and T cell activation.
  • CD47 interacts with several membrane integrins, most commonly integrin ⁇ V ⁇ 3, resulting in complexes that affect a range of cell functions including adhesion, spreading and migration. Binding of the secreted ligand thrombospondin-1 (TSP-1) to CD47 influences several fundamental cellular functions including cell migration and adhesion, cell proliferation or apoptosis, and plays a role in the regulation of angiogenesis and inflammation. With respect to phagocytosis, CD47 acts as a “don't eat me” signal by binding to SIRP ⁇ on macrophages of the immune system and has been found to be upregulated in certain hematologic cancers and indicated in evasion of tumor surveillance, making it a therapeutic target for cancer.
  • TSP-1 secreted ligand thrombospondin-1
  • a rodent described herein may comprise an hCD47 gene and/or otherwise express an hCD47 polypeptide.
  • the hCD47 polypeptide may be a full-length human polypeptide (e.g., wildtype human polypeptide) or comprise a functional fragment thereof.
  • the hCD47 polypeptide may be a fully human CD47 polypeptide.
  • a rodent may express a humanized (chimeric) CD47 polypeptide.
  • the humanized CD47 polypeptide may comprise a human extracellular domain and an endogenous rodent (e.g., mouse) intracellular domain (e.g., the intracellular portion of a rodent CD47 protein).
  • the chimeric polypeptide may be a rodent CD47 polypeptide having its extracellular domain, or a substantial portion thereof, replaced with a human CD47 extracellular domain.
  • the rodent may be a rodent (e.g., a mouse) having an hCD47 gene that comprises exons 2-7 of a human CD47 gene (e.g., replacing native exons 2-7 within the endogenous rodent Cd47 locus of the genome of the genetically modified rodent).
  • the hCD47 gene may comprise exon 1 and any exons downstream of exon 7 of an endogenous rodent Cd47 gene (e.g., the native exons within the endogenous rodent Cd47 locus of the genome of the genetically modified rodent).
  • the genetically modified animal may be heterozygous or homozygous for the hCD47 gene.
  • the genetically modified rodent may be modified in such a manner that it does not express any wild-type rodent CD47 polypeptide.
  • a genetically modified rodent embryonic stem cell comprising one or more copies of the hCD47 gene described herein or an embryo comprising such an embryonic stem cell (e.g., for making a genetically modified rodent comprising an hCD47 gene as described herein).
  • the hCD47 gene or the rodent, embryo, or embryonic stem cell comprising the hCD47 gene may be any of those described in U.S. Pat. No. 9,730,435 to McWhirter, et al., issued on Aug.
  • IL-3 (NCBI Gene IDs: 3562 (homo sapiens), Gene symbol: IL3; 16187 (mus musculus), Gene symbol: Il3) is a cytokine produced by activated T cells, monocytes, macrophages and stroma cells and promotes the proliferation and differentiation of a broad range of myeloid progenitor cells, including those that give rise to granulocytes, monocytes, and dendritic cells, in conjunction with other cytokines (e.g., EPO, GM-CSF and IL-6).
  • cytokines e.g., EPO, GM-CSF and IL-6.
  • a rodent described herein may comprise an hIL3 gene and/or otherwise express an hIL-3 polypeptide.
  • the hIL-3 polypeptide may be a full-length human polypeptide (e.g., wildtype human polypeptide) or comprise a functional fragment thereof.
  • the hIL-3 polypeptide may be a fully human IL-3 polypeptide.
  • the hIL3 gene may comprise a human IL35’ UTR.
  • the hIL3 gene may comprise a human IL33’ UTR.
  • the hIL3 gene may comprise a human IL35’ UTR, followed by a human IL3 coding region, followed by a human IL33’ UTR.
  • the rodent may comprise a replacement of a nucleic acid comprising the rodent’s endogenous Il35’ UTR, endogenous Il3 coding region, and endogenous Il33’ UTR with a nucleic acid comprising a human I-35’ UTR, human IL3 coding region, and human IL33’ UTR.
  • the genetically modified animal may be heterozygous or homozygous for the hIL3 gene.
  • the genetically modified rodent may be modified in such a manner that it does not express any wild-type rodent IL-3 polypeptide.
  • a genetically modified rodent embryonic stem cell comprising one or more copies of the hIL3 gene described herein or an embryo comprising such an embryonic stem cell (e.g., for making a genetically modified rodent comprising an hIL3 gene as described herein).
  • the hIL3 gene or the rodent, embryo, or embryonic stem cell comprising the hIL3 gene may be any of those described in U.S. Pat. No. 8,541,646 to Stevens, et al., issued on Sep.
  • GM-CSF Granulocyte-macrophage colony-stimulating factor
  • GM-CSF Granulocyte-macrophage colony-stimulating factor
  • Gene symbol: CSF2; 12981 (mus musculus), Gene symbol: Csf2 is a cytokine secreted by macrophages, T cells, mast cells and natural killer cells in response to proinflammatory stimuli and stimulates hematopoietic stem and progenitor cells to produce granulocytes (neutrophils, eosinophils, and basophils) and monocytes.
  • a rodent described herein may comprise an hCSF2 gene and/or otherwise express an hGM-CSF polypeptide.
  • the hGM-CSF polypeptide may be a full-length human polypeptide (e.g., wildtype human polypeptide) or comprise a functional fragment thereof.
  • the hCSF2 polypeptide may be a fully human GM-CSF polypeptide.
  • the hCSF2 gene may comprise a human CSF25’ UTR. According to certain aspects of the disclosure, the hCSF2 gene may comprise a human CSF23’ UTR. According to certain aspects of the disclosure, the hCSF2 gene may comprise a human CSF25’ UTR, followed by a human CSF2 coding region, followed by a human CSF23’ UTR.
  • the rodent may comprise a replacement of a nucleic acid comprising the rodent’s endogenous Csf25’ UTR, endogenous Csf2 coding region, and endogenous Csf23’ UTR with a nucleic acid comprising a human CSF25’ UTR, human CSF2 coding region, and human CSF23’ UTR.
  • the genetically modified animal may be heterozygous or homozygous for the hCSF2 gene.
  • the genetically modified rodent may be modified in such a manner that it does not express any wild-type rodent GM-CSF polypeptide.
  • M-CSF Macrophage colony-stimulating factor
  • NCBI Gene IDs: 1435 homo sapiens
  • Gene symbol: Csf1 is a cytokine that helps modulate the proliferation of monocytes, macrophages, and bone marrow progenitor cells as well as promote the differentiation of monocytes and macrophages.
  • Expression of human or humanized M-CSF (hM-CSF) may be particularly useful for promoting the proper development and/or function of human monocytes and macrophages within a rodent.
  • a rodent described herein may comprise an hCSF1 gene and/or otherwise express an hM-CSF polypeptide.
  • the hM-CSF polypeptide may be a full-length human polypeptide (e.g., wildtype human polypeptide) or comprise a functional fragment thereof.
  • the hM-CSF polypeptide may be a fully human M-CSF polypeptide.
  • the mature hM-CSF polypeptide (lacking a signal peptide) may be fully human.
  • the hCSF1 gene may comprise an endogenous rodent Csf15’ UTR.
  • the hCSF1 gene may comprise a human CSF13’ UTR.
  • the hCSF1 gene may comprise an endogenous rodent Csf15’ UTR, followed by an CSF1 coding region that encodes an M-CSF polypeptide having a fully human mature polypeptide sequence, followed by a human CSF13’ UTR.
  • the rodent may be a rodent (e.g., a mouse) having an hCSF1 gene that comprises exons 2-9 of a human CSF1 gene (e.g., replacing native exons 2-9 within the endogenous rodent Csf1 locus of the genome of the genetically modified rodent).
  • a genetically modified rodent embryonic stem cell comprising one or more copies of the hCSF1 gene described herein or an embryo comprising such an embryonic stem cell (e.g., for making a genetically modified rodent comprising an hCSF1 gene as described herein).
  • the hCSF1 gene or the rodent, embryo, or embryonic stem cell comprising the hCSF1 gene may be any of those described in U.S. Pat. No. 8,847,004 to Murphy, et al., issued on Sep. 30, 2014, which is herein incorporated by reference in its entirety, upon which additional modifications may be made in accordance with the disclosure herein.
  • TPO Thrombopoietin
  • THPO THPO
  • Thpo thrombopoietin receptor
  • c-Mpl receptor thrombopoietin receptor
  • Thpo is a glycoprotein hormone produced by the liver and kidney that binds thrombopoietin receptor (c-Mpl receptor) and regulates the production of platelets via stimulating the production and differentiation of megakaryocytes.
  • TPO supports the expansion and self-renewal of hematopoietic stem cells.
  • Expression of human or humanized TPO (hTPO) may be particularly useful for promoting the proper development and/or function of human megakaryocytes and thrombocytes (platelets) within a rodent.
  • a genetically modified rodent embryonic stem cell comprising one or more copies of the hTHPO gene described herein or an embryo comprising such an embryonic stem cell (e.g., for making a genetically modified rodent comprising an hTHPO gene as described herein).
  • the hTHPO gene or the rodent, embryo, or embryonic stem cell comprising the hTHPO gene may be any of those described in U.S. Pat. No. 9,301,509 to Stevens, et al., issued on Apr. 5, 2016, which is herein incorporated by reference in its entirety, upon which additional modifications may be made in accordance with the disclosure herein.
  • EPO Erythropoietin
  • NCBI Gene IDs: 2056 (homo sapiens), Gene symbol: EPO; 13856 (mus musculus), Gene symbol: Epo) supports the development of erythroid lineage cells in the bone marrow and enhances terminal erythropoiesis.
  • Expression of human or humanized EPO (hEPO) may be particularly useful for promoting the proper development and/or function of human erythrocytes (red blood cells) within a rodent.
  • a rodent described herein may comprise an hEPO gene and/or otherwise express an hEPO polypeptide.
  • the rodent may comprise a replacement of a nucleic acid comprising the rodent’s endogenous Epo coding region and endogenous Epo 3’ UTR with a nucleic acid comprising a human EPO coding region and a human EPO 3’ UTR.
  • the genetically modified animal may be heterozygous or homozygous for the hEPO gene.
  • the genetically modified rodent may be modified in such a manner that it does not express any wild- type rodent EPO polypeptide.
  • a genetically modified rodent embryonic stem cell comprising one or more copies of the hEPO gene described herein or an embryo comprising such an embryonic stem cell (e.g., for making a genetically modified rodent comprising an hEPO gene as described herein).
  • the hEPO gene or the rodent, embryo, or embryonic stem cell comprising the hEPO gene may be any of those described in U.S. Pat. No. 9,301,509 to Stevens, et al., issued on Apr. 5, 2016, which is herein incorporated by reference in its entirety, upon which additional modifications may be made in accordance with the disclosure herein.
  • IL-6 (NCBI Gene IDs: 3569 (homo sapiens); Gene symbol: IL6; 16193 (mus musculus), Gene symbol: Il6) is a pleiotropic cytokine that mediates B cell differentiation and can promote T cell differentiation, activation, and proliferation, including the differentiation of T cells into cytotoxic T cells in the presence of IL-2.
  • IL-6 is secreted by various cell types, including immune cells and cancer cells. Expression of human or humanized IL-6 (hIL-6) may be particularly useful for promoting the proper development and/or function of human T cells and, particularly, human B cells within a rodent.
  • a rodent described herein may comprise an hIL6 gene and/or otherwise express an hIL-6 polypeptide.
  • the hIL-6 polypeptide may be a full-length human polypeptide (e.g., wildtype human polypeptide) or comprise a functional fragment thereof.
  • the hIL-6 polypeptide may be a fully human IL-6 polypeptide.
  • the hIL6 gene may comprise an endogenous rodent Il65’ UTR.
  • the hIL6 gene may comprise a human IL63’ UTR.
  • the hIL6 gene may comprise an endogenous rodent Il65’ UTR, followed by a human IL6 coding region, followed by a human IL63’ UTR.
  • the rodent may comprise a replacement of a nucleic acid comprising the rodent’s endogenous Il6 coding region and endogenous Il63’ UTR with a nucleic acid comprising a human IL6 coding region and human IL63’ UTR.
  • the genetically modified animal may be heterozygous or homozygous for the hIL6 gene.
  • the genetically modified rodent may be modified in such a manner that it does not express any wild-type rodent IL-6 polypeptide.
  • a genetically modified rodent embryonic stem cell comprising one or more copies of the hIL6 gene described herein or an embryo comprising such an embryonic stem cell (e.g., for making a genetically modified rodent comprising an hIL-6 gene as described herein).
  • the hIL6 gene or the rodent, embryo, or embryonic stem cell comprising the hIL6 gene may be any of those described in U.S. Pat. No. 8,878,001 to Wang, et al., issued on May 9, 2013, which is herein incorporated by reference in its entirety, upon which additional modifications may be made in accordance with the disclosure herein.
  • IL-6 receptor is the receptor for IL-6 and is expressed in activated B cells and resting T cells.
  • the IL6 receptor is a protein complex consisting of an IL-6 receptor subunit (IL6R ⁇ ; NCBI Gene IDs: 3570 (homo sapiens), Gene symbol: IL6R; 16194 (mus musculus), Gene symbol: Il6ra) and interleukin 6 signal transducer Glycoprotein 130.
  • the hIL-6R ⁇ polypeptide may be a fully human IL-6R ⁇ polypeptide.
  • the hIL-6R ⁇ polypeptide comprises a human extracellular domain (e.g., the extracellular portion of a human IL-6R ⁇ protein).
  • the hIL-6R ⁇ polypeptide may comprise the coding portion of human exon 1 (beginning at the start codon, ATG) through human exon 8.
  • a rodent may express a humanized (chimeric) IL-6R ⁇ polypeptide.
  • the humanized IL-6R ⁇ polypeptide may comprise a human extracellular domain and an endogenous rodent (e.g., mouse) intracellular domain (e.g., the intracellular portion of a rodent IL-6R ⁇ protein).
  • the chimeric polypeptide may be a rodent IL-6R ⁇ polypeptide having its extracellular domain, or a substantial portion thereof, replaced with a human IL-6R ⁇ extracellular domain.
  • the rodent may be a rodent (e.g., a mouse) having an hIL6R gene that comprises the coding portion of human exon 1 (beginning at the start codon, ATG) through human exon 8 of a human IL6R gene (e.g., replacing the coding portion of the endogenous rodent exon 1 through the endogenous exon 8 within the endogenous rodent Il6ra locus of the genome of the genetically modified rodent).
  • a rodent e.g., a mouse having an hIL6R gene that comprises the coding portion of human exon 1 (beginning at the start codon, ATG) through human exon 8 of a human IL6R gene (e.g., replacing the coding portion of the endogenous rodent exon 1 through the endogenous exon 8 within the endogenous rodent Il6ra locus of the genome of the genetically modified rodent).
  • the hIL6R gene may comprise an endogenous rodent Il6ra 5’ UTR, endogenous exons 9 and 10 of an endogenous rodent Il6ra gene, and an endogenous Il6ra 3’ UTR (e.g., the native UTRs and native exons 9 and 10 within the endogenous rodent Il6ra locus of the genome of the genetically modified rodent).
  • the genetically modified animal may be heterozygous or homozygous for the hIL6R gene.
  • the genetically modified rodent may be modified in such a manner that it does not express any wild- type rodent IL-6R ⁇ polypeptide.
  • a genetically modified rodent embryonic stem cell comprising one or more copies of the hIL6R gene described herein or an embryo comprising such an embryonic stem cell (e.g., for making a genetically modified rodent comprising an hIL6R gene as described herein).
  • the hIL6R gene or the rodent, embryo, or embryonic stem cell comprising the hIL6R gene may be any of those described in U.S. Pat. No. 9,125,386 to Wang, et al., issued on Sep. 8, 2015, which is herein incorporated by reference in its entirety, upon which additional modifications may be made in accordance with the disclosure herein.
  • IL-7 (NCBI Gene ID: 3574 (homo sapiens), Gene symbol: IL7; 16196 (mus musculus), Gene symbol: Il7) is a cytokine that promotes the differentiation of lymphoid progenitor cells and the proliferation of lymphoid lineage cells. It is essential for development of immature B and T cells and, to some degree, mature T cells. IL-7 is produced by epithelial cells in the thymus and intestine, in keratinocytes, liver, and dendritic cells-but not by normal lymphocytes.
  • the rodent may be a rodent (e.g., a mouse) having an hIL7 gene that comprises exons 2-6 of a human IL7 gene (e.g., replacing native exons 2-5 within the endogenous rodent Il7 locus of the genome of the genetically modified rodent).
  • the hIL7 gene may comprise exon 1 of an endogenous rodent Il7 gene (e.g., the native exon within the endogenous rodent Il7 locus of the genome of the genetically modified rodent).
  • the genetically modified animal may be heterozygous or homozygous for the hIL7 gene.
  • the genetically modified rodent may be modified in such a manner that it does not express any wild-type rodent IL-7 polypeptide.
  • a genetically modified rodent embryonic stem cell comprising one or more copies of the hIL7 gene described herein or an embryo comprising such an embryonic stem cell (e.g., for making a genetically modified rodent comprising an hIL7 gene as described herein).
  • the hIL7 gene or the rodent, embryo, or embryonic stem cell comprising the hIL7 gene may be any of those described in U.S. Pat. No. 8,962,913 to Murphy, issued on Feb. 24, 2015, which is herein incorporated by reference in its entirety, upon which additional modifications may be made in accordance with the disclosure herein.
  • BAFF BAFF receptor
  • BAFF-R BAFF receptor
  • TACI transmembrane activator and calcium modulator and cyclophilin ligand interactor
  • BCMA B cell maturation antigen
  • BAFF plays a role in B cell activation and development.
  • Expression of human or humanized BAFF (hBAFF) may be particularly useful for promoting the development and long-term survival of human B cells in rodents, including antigen-specific B cells (e.g., in immunized animals engrafted with human HSCs), and adoptively transferred mature B cells.
  • a rodent described herein may comprise an hTNFSF13B gene and/or otherwise express an hBAFF polypeptide.
  • the hBAFF polypeptide may be a full-length human polypeptide (e.g., wildtype human polypeptide) or comprise a functional fragment thereof. According to certain aspects of the disclosure, the hBAFF polypeptide may be a fully human BAFF polypeptide. According to certain aspects of the disclosure, the hBAFF polypeptide comprises a human extracellular domain (e.g., the extracellular portion of a human BAFF protein).
  • the hBAFF polypeptide may comprise residues 142-285 of the amino acid sequence set forth in NCBI Ref Seq: NP_006564.1, which is herein incorporated by reference in its entirety, or comprise an amino acid sequence that is substantially identical (e.g., at least 90, 95, 96, 97, 98, or 99% identical) to residues 142-285.
  • a rodent may express a humanized (chimeric) BAFF polypeptide.
  • the humanized BAFF polypeptide may comprise a human extracellular domain and an endogenous rodent (e.g., mouse) intracellular domain (e.g., the intracellular portion of a rodent BAFF protein).
  • the chimeric polypeptide may be a rodent BAFF polypeptide having its extracellular domain, or a substantial portion thereof, replaced with a human BAFF extracellular domain.
  • the rodent may be a rodent (e.g., a mouse) having an hTNFSF13B gene that comprises exons 3-6 of a human TNFSF13B gene (e.g., replacing a nucleic acid sequence comprising native exons 3-7 or native exons 3-6 as well as the coding portion of native exon 7 within the endogenous rodent Tnfsf13b locus of the genome of the genetically modified rodent).
  • the hTNFSF13B gene may comprise a 3’ portion of intron 2 of a human TNFSF13B gene (e.g., replacing a 3’ portion of native intron 2 within the endogenous rodent Tnfsf13b locus of the genome of the genetically modified rodent).
  • the hTNFSF13B gene may comprise exons 1 and 2 of an endogenous rodent Tnfsf13b gene (e.g., the native exons within the endogenous rodent Tnfsf13b locus of the genome of the genetically modified rodent).
  • the hTNFSF13B gene may comprise a 5’ portion of intron 2 of an endogenous rodent Tnfsf13b gene (e.g., a 5’ portion of the native intron 2 within the endogenous rodent Tnfsf13b locus of the genome of the genetically modified rodent).
  • the 5’ portion may comprise a splice donor site.
  • the hTNFSF13B gene may comprise a 3’ portion of exon 7 of an endogenous rodent Tnfsf13b gene (e.g., a 3’ portion of the native exon 7 within the endogenous rodent Tnfsf13b locus of the genome of the genetically modified rodent).
  • the genetically modified animal may be heterozygous or homozygous for the hTNFSF13B gene.
  • the genetically modified rodent may be modified in such a manner that it does not express any wild-type rodent BAFF polypeptide.
  • a genetically modified rodent embryonic stem cell comprising one or more copies of the hTNFSF13B gene described herein or an embryo comprising such an embryonic stem cell (e.g., for making a genetically modified rodent comprising an hTNFSF13B gene as described herein).
  • the hTNFSF13B gene or the rodent, embryo, or embryonic stem cell comprising the hTNFSF13B gene may be any of those described in U.S. Pat.
  • APRIL transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B cell maturation antigen (BCMA).
  • TACI transmembrane activator and calcium modulator and cyclophilin ligand interactor
  • BCMA B cell maturation antigen
  • APRIL plays a role in B cell and T cell activation and survival, and, notably, stimulates the growth of tumor cells in vitro and in vivo.
  • hAPRIL human or humanized APRIL
  • rodents including antigen-specific B cells (e.g., in immunized animals engrafted with human HSCs), and adoptively transferred mature B cells.
  • a rodent described herein may comprise an hTNFSF13 gene and/or otherwise express an hAPRIL polypeptide.
  • the hAPRIL polypeptide may be a full-length human polypeptide (e.g., wildtype human polypeptide) or comprise a functional fragment thereof.
  • the hAPRIL polypeptide may be a fully human APRIL polypeptide.
  • the humanized APRIL polypeptide may comprise a human extracellular domain and an endogenous rodent (e.g., mouse) intracellular domain (e.g., the intracellular portion of a rodent APRIL protein).
  • the chimeric polypeptide may be a rodent APRIL polypeptide having its extracellular domain, or a substantial portion thereof, replaced with a human APRIL extracellular domain.
  • the rodent may be a rodent (e.g., a mouse) having an hTNFSF13 gene that comprises exons 2-6 of a human TNFSF13 gene (e.g., replacing a nucleic acid sequence comprising native exons 2-6 or native exons 2-5 as well as the coding portion of native exon 6 within the endogenous rodent Tnfsf13 locus of the genome of the genetically modified rodent).
  • the hTNFSF13 gene may comprise a 3’ portion of intron 1 of a human TNFSF13 gene (e.g., replacing a 3’ portion of native intron 1 within the endogenous rodent Tnfsf13 locus of the genome of the genetically modified rodent).
  • the hTNFSF13 gene may comprise exon 1 of an endogenous rodent Tnfsf13 gene (e.g., the native exon within the endogenous rodent Tnfsf13 locus of the genome of the genetically modified rodent).
  • the hTNFSF13 gene may comprise a 5’ portion of intron 1 of an endogenous rodent Tnfsf13 gene (e.g., a 5’ portion of the native intron 1 within the endogenous rodent Tnfsf13 locus of the genome of the genetically modified rodent).
  • the 5’ portion may comprise a splice donor site.
  • the hTNFSF13 gene may comprise a 3’ portion of exon 6 of an endogenous rodent Tnfsf13 gene (e.g., a 3’ portion of the native exon 6 within the endogenous rodent Tnfsf13 locus of the genome of the genetically modified rodent).
  • the 3’ portion of endogenous exon 6 may comprise an endogenous Tnfsf133’ UTR.
  • the hTNFSF13 gene may comprise exon 1 of an endogenous rodent Tnfsf13 gene (e.g., exon 1 through a 5’ portion of intron 1), followed by exons 2-6 of a human TNFSF13 gene (e.g., a 3’ portion of intron 1 through exon 6, including a human TNFSF133’ UTR), followed by a 3’ portion of exon 6 of an endogenous rodent Tnfsf13 gene (including an endogenous Tnfsf133’ UTR).
  • the genetically modified animal may be heterozygous or homozygous for the hTNFSF13 gene.
  • the genetically modified rodent may be modified in such a manner that it does not express any wild-type rodent APRIL polypeptide.
  • a genetically modified rodent embryonic stem cell comprising one or more copies of the hTNFSF13 gene described herein or an embryo comprising such an embryonic stem cell (e.g., for making a genetically modified rodent comprising an hTNFSF13 gene as described herein).
  • the hTNFSF13 gene or the rodent, embryo, or embryonic stem cell comprising the hTNFSF13 gene may be any of those described in U.S. Pat. No. 9,730,435 to McWhirter, et al., issued on Aug.
  • CXCL13 [00152] C-X-C motif chemokine ligand 13 (CXCL13; NCBI Gene IDs: 10563 (homo sapiens), Gene symbol: CXCL13; 55985 (mus musculus), Gene symbol: Cxcl13) is a protein ligand selectively chemotactic for B cells and follicular B helper T cells (TFH cells) that elicits its effects by interacting with chemokine receptor CXCR5.
  • CXCL13 NCBI Gene IDs: 10563 (homo sapiens)
  • Gene symbol CXCL13; 55985 (mus musculus)
  • Cxcl13 is a protein ligand selectively chemotactic for B cells and follicular B helper T cells (TFH cells) that elicits its effects by interacting with chemokine receptor CXCR5.
  • CXCL13 is strongly expressed in the liver, spleen, lymph nodes, and Peyer's patches and is believed to be a critical chemokine for attracting B cells and TFH cells to the germinal center for B cell activation, class switching, and somatic hyper-mutation.
  • Expression of human or humanized CXCL13 may be particularly useful for promoting the development and long-term survival of human B cells in rodents, including antigen-specific B cells (e.g., in immunized animals engrafted with human HSCs), and adoptively transferred mature B cells, as well as for engrafting cancer or tumor cells, such as lymphocytic leukemia cells (e.g., CLL or ALL).
  • the hCXCL13 polypeptide may comprise residues 30-91 of the amino acid sequence set forth in NCBI Ref Seq: NP_006410.1, which is herein incorporated by reference in its entirety, or comprise an amino acid sequence that is substantially identical (e.g., at least 90, 95, 96, 97, 98, or 99% identical) to residues 30-91.
  • a rodent may express a humanized (chimeric) CXCL13 polypeptide.
  • the chimeric polypeptide may be a rodent CD47 polypeptide having its chemokine IL-8 like domain, or a substantial portion thereof, replaced with a human CXCL13 chemokine IL-8 like domain.
  • the rodent may be a rodent (e.g., a mouse) having an hCXCL13 gene that comprises exons 3-5 of a human CXCL13 gene (e.g., replacing a nucleic acid sequence comprising native exons 2-4 or native exons 2 and 3 as well as the coding portion of native exon 4 within the endogenous rodent Cxcl13 locus of the genome of the genetically modified rodent).
  • the hCXCL13 gene may comprise a 3’ portion of intron 2 of a human CXCL13 gene (e.g., replacing a 3’ portion of native intron 1 within the endogenous rodent Cxcl13 locus of the genome of the genetically modified rodent).
  • the hCXCL13 gene may comprise a 5’ portion of intron 1 of an endogenous rodent Cxcl13 gene (e.g., a 5’ portion of the native intron 1 within the endogenous rodent Cxcl13 locus of the genome of the genetically modified rodent).
  • the 5’ portion may comprise a splice donor site.
  • the hCXCL13 gene may comprise a 3’ portion of exon 4 of an endogenous rodent Cxcl13 gene (e.g., a 3’ portion of the native exon 4 within the endogenous rodent Cxcl13 locus of the genome of the genetically modified rodent).
  • the 3’ portion of endogenous exon 4 may comprise an endogenous Cxcl133’ UTR.
  • the genetically modified rodent may be modified in such a manner that it does not express any wild- type rodent CXCL13 polypeptide.
  • a genetically modified rodent embryonic stem cell comprising one or more copies of the hCXCL13 gene described herein or an embryo comprising such an embryonic stem cell (e.g., for making a genetically modified rodent comprising an hCXCL13 gene as described herein).
  • the hCXCL13 gene or the rodent, embryo, or embryonic stem cell comprising the hCXCL13 gene may be any of those described in U.S. Pat. App. Pub. No.
  • HMOX-1 Heme oxygenase (HMOX) metabolizes heme and releases free iron, carbon monoxide, and biliverdin, which quickly undergoes conversion to bilirubin.
  • HMOX-1 NCBI Gene IDs: 3162 (homo sapiens), Gene symbol: HMOX1; 15368 (mus musculus), Gene symbol: Hmox1), which is inducible, and HMOX-2, which is constitutively expressed in most tissues.
  • Hmox1 -/- mice have decreased macrophages (F4/80+) in spleen, liver, blood and bone marrow (BM), but still have myeloid cells (CD11b+). Lack of HMOX-1 renders erthyrophagocytic macrophages unable to process heme and causes intracellular toxicity due to heme build-up.
  • the genetically modified rodent may comprise a null mutation in the rodent Hmox1 gene at the rodent Hmox1 gene locus.
  • the null mutation comprises a deletion, an insertion, and/or a substitution in the rodent Hmox1 gene at the rodent Hmox1 gene locus.
  • the endogenous rodent Hmox1 locus comprises a null mutation, and hence, a null allele.
  • a null allele is a mutant copy of a gene that completely lacks that gene’s normal function. This can be the result of the complete absence of the gene product (protein, RNA) at the molecular level, or the expression of a non-functional gene product. At the phenotypic level, a null allele is indistinguishable from a deletion of the entire locus.
  • the rodent may be a rodent (e.g., a mouse) having an Hmox1 null mutation that is a deletion of at least exons 3-5.
  • the null mutation is a deletion of the full Hmox1 endogenous coding sequence.
  • the rodent may comprise the same null mutation for all the alleles.
  • the rodent may comprise different null mutations for different alleles.
  • Mouse Hmox1 is located on Chromosome 8, GRCm39, NC_000074.7 (75820246-75827221), and the mouse Hmox1 coding sequence may be found at Genbank Accession No. NM_010442.2.
  • the mouse Hmox1 locus includes 5 exons, with exons 1-5 being coding exons.
  • the genetically modified animals provided herein may be mice, and one or more of exons 1-5 of the mouse Hmox1 gene may be deleted or mutated in the genetically modified mice.
  • the genomic locus of the mouse Hmox1 gene e.g., introns, 3' and/or 5' untranslated sequence (UTRs) are also deleted or mutated.
  • the whole regions of the mouse Hmox1 genomic locus are deleted.
  • the whole genomic region from the start codon to the stop codon of the mouse Hmox1 gene is deleted.
  • the genetically modified mice may comprise a deletion of ⁇ 7 kb of mouse sequence (GRCm38 coordinates chr8: 75093750- 75100019).
  • engrafted rodents or rodents for engraftment e.g., mice or rats
  • engrafted rodents or rodents for engraftment comprise a Recombination-activating gene 2 (Rag2) gene knock-out and/or an Interleukin 2 receptor gamma (Il2rg) gene knock-out.
  • engrafted rodents or rodents for engraftment further comprise a human or humanized signal regulatory protein alpha (SIRPA) knock-in.
  • SIRPA signal regulatory protein alpha
  • an engrafted rodent or rodent for engraftment comprises a Rag2 gene knock-out, an Il2rg gene knock-out, and a human or humanized SIRPA knock-in.
  • engrafted rodents or rodents for engraftment are Rag2 -/- ; Il2r ⁇ -/- ; SIRPA h/h .
  • an engrafted rodent or rodent for engraftment comprises a Rag2 gene knock-out, an Il2rg gene knock-out, a human or humanized SIRPA knock-in, and one or more additional modifications.
  • a genetically modified rodent of the present disclosure comprises, in its genome: (i) a human or humanized SIRPA gene, (ii) a human or humanized Il15 gene, (iii) a homozygous knockout mutation of an endogenous Rag, e.g., endogenous Rag2, gene, and (iv) a homozygous knockout mutation of an endogenous Il2r, e.g., endogenous Il2r ⁇ , gene.
  • Such a genetically modified rodent can be further genetically modified, e.g., to comprise one or more human or humanized component of the immune system, e.g., to comprise a human or humanized MHC molecule as described herein.
  • a genetically modified rodent of the present disclosure comprises, in its genome: (i) a nucleotide sequence, e.g., recombinant nucleic acid, encoding (at least) an antigen presenting portion of a human or humanized MHC, e.g., classical HLA, molecule, (ii) a human or humanized SIRPA gene, (iii) a human or humanized IL15 gene, (iv) a homozygous knockout mutation of an endogenous Rag, e.g., endogenous Rag2, gene, and (v) a homozygous knockout mutation of an endogenous Il2r, e.g., endogenous Il2r ⁇ , gene.
  • a nucleotide sequence e.g., recombinant nucleic acid
  • an antigen presenting portion of a human or humanized MHC e.g., classical HLA, molecule
  • a human or humanized SIRPA gene e.g.
  • the genetically modified rodent of the present invention comprises: (a) in its genome, (i) a first recombinant nucleic acid encoding (at least) an antigen presenting portion of a human or humanized MHC, e.g., classical HLA, molecule, (ii) a human or humanized SIRPA gene, (iii) a homozygous knockout mutation of an endogenous Rag, e.g., endogenous Rag2, gene, and (iv) a homozygous knockout mutation of an endogenous Il2r, e.g., endogenous Il2r ⁇ , gene, and (b) in its periphery, a human T cell, wherein the human T cell is genetically modified to express
  • an engineered human T cell as described herein expresses a recombinant nucleic acid that encodes (at least) a recombinant human TCR variable domain. In some embodiments, an engineered human T cell as described herein expresses a recombinant nucleic acid that encodes (at least) a recombinant human TCR ⁇ variable domain and (at least) a recombinant human TCR ⁇ variable domain. In some embodiments, an engineered human T cell as described herein expresses a recombinant nucleic acid that encodes a recombinant human TCR, i.e., variable and constant domains of the TCR ⁇ and ⁇ chains.
  • the recombinant human TCR variable domain binds an antigen presented in the context of the antigen presenting portion of the human or humanized MHC, e.g., classical HLA, molecule of the genetically modified rodent.
  • the recombinant human TCR is MHC- restricted, e.g., HLA-restricted, e.g., HLA-DQ2.5-restricted.
  • the recombinant human TCR is antigen-specific, e.g., gliadin-specific, e.g., ⁇ 1 gliadin-specific.
  • the recombinant human TCR variable domain is an HLA-restricted antigen- specific, e.g., HLA-DQ2.5-restricted ⁇ 1-gliadin-specific, TCR variable domain.
  • the engineered T cell does not express endogenous TCR genes.
  • a method of making the genetically modified rodent as described herein comprises introducing a human T cell into a genetically modified rodent as described herein (e.g., comprising in its genome a first recombinant nucleic acid encoding at least an antigen presenting portion of a classical HLA molecule and one or more genetic modifications that enhance the adoptive transfer of human cell, e.g., human T cells), wherein the human T cell expresses a second recombinant nucleic acid that encodes (at least) a recombinant human TCR variable domain that binds an antigen presented in the context of the antigen presenting portion of the classical HLA molecule.
  • generating a genetically modified rodent as described herein may comprise a combination of breeding and homologous recombination in ES cells, e.g., breeding an rodent to another rodent, wherein some or all of the rodents may be generated from ES cells genetically modified via a single homologous recombination or sequential homologous recombination events, and wherein some ES cell may be isolated from a rodent comprising one or more of the genetic modifications disclosed herein.
  • the method utilizes a targeting construct made using VELOCIGENE® technology, introducing the construct into ES cells, and introducing targeted ES cell clones into a mouse embryo using VELOCIMOUSE® technology, as described in the Examples.
  • Targeting constructs may comprise 5’ and/or 3’ homology arms that target the endogenous sequence to be replaced, an insert sequence (that replaces the endogenous sequence) and one or more selection cassettes.
  • a selection cassette is a nucleotide sequence inserted into a targeting construct to facilitate selection of cells (e.g., ES cells) that have integrated the construct of interest.
  • cells e.g., ES cells
  • suitable selection cassettes are known in the art. Commonly, a selection cassette enables positive selection in the presence of a particular antibiotic (e.g., Neo, Hyg, Pur, CM, SPEC, etc.).
  • a selection cassette may be flanked by recombination sites, which allow deletion of the selection cassette upon treatment with recombinase enzymes.
  • a selection cassette may be located anywhere in the construct outside the coding region. In one embodiment, the selection cassette is located at the 5’ end the human DNA fragment. In another embodiment, the selection cassette is located at the 3’ end of the human DNA fragment. In another embodiment, the selection cassette is located within the human DNA fragment. In another embodiment, the selection cassette is located within an intron of the human DNA fragment. In another embodiment, the selection cassette is located at the junction of the human and mouse DNA fragment.
  • non-human animals e.g., mice bearing the genetic modification of interest
  • non-human animals e.g., mice
  • Other assays that identify a specific nucleotide or amino acid sequence in the genetically modified animals are known to those skilled in the art.
  • the method comprises: (a) breeding a genetically modified rodent comprising a recombinant nucleic acid encoding (at least) an antigen presenting portion of a classical HLA molecule with a genetically modified rodent comprising one or more additional genetic modifications as described herein, e.g., one or more genetic modifications that enhance the adoptive transfer of human cell, e.g., human T cells, such that the resulting progeny comprise a recombinant nucleic acid encoding (at least) an antigen presenting portion of a classical HLA molecule and one or more additional genetic modifications as described herein, and (b) introducing into the genetically modified rodent a genetically modified human T cell that expresses a second recombinant nucleic acid that encodes (at least) a recombinant human TCR variable domain that binds an antigen presented in the context of the antigen presenting portion of the classical HLA molecule.
  • a genetically modified rodent comprising a recombinant
  • the method comprises administering an antigen to a genetically modified rodent as described herein and determining the absence or presence of activated human T cells in the genetically modified rodent.
  • the presence of activated human T cells in the genetically modified rodent indicates the antigen is pathogenic.
  • administering comprises oral gavage with a gliadin peptide.
  • administration to an animal subject may be bronchial (including by bronchial instillation), buccal, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal and/or vitreal.
  • administration may involve intermittent dosing.
  • the AIM is selected from the group consisting of Ki67, IFNG, GZMB, 4-1BB, HLA-DR, ICOS, PD1, CD39, CCL5, and any combination thereof.
  • the method comprises introducing an antigen into a genetically modified rodent as described herein to activate the human T cell into a human effector T cell, administering the therapeutic candidate to the genetically modified rodent, and determining whether the therapeutic candidate reduces, prevents, or inhibits activation of the human T cell into a human effector T cell.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Immunology (AREA)
  • Genetics & Genomics (AREA)
  • General Health & Medical Sciences (AREA)
  • Biotechnology (AREA)
  • Wood Science & Technology (AREA)
  • Biomedical Technology (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Cell Biology (AREA)
  • Medicinal Chemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Microbiology (AREA)
  • Toxicology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biophysics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Environmental Sciences (AREA)
  • Hematology (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Animal Husbandry (AREA)
  • Biodiversity & Conservation Biology (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

Provided herein are genetically modified rodent models of disease, wherein the rodent expresses at least an antigen presenting portion of a classical human leukocyte antigen (HLA) molecule, and comprises, in its periphery, human T cells, e.g., engineered human T cells genetically modified to express at least a recombinant human T cell receptor (TCR) variable domain that binds an antigen presented in the context of the antigen presenting portion of the HLA. Also provided herein are methods of making and using the same, e.g., for identifying therapeutic candidates for treatment of a disorder associated with an HLA-peptide-TCR interaction.

Description

RODENT MODELS OF DISEASE CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of priority to U.S. Provisional Application No. 63/575,454, filed April 5, 2024, U.S. Provisional Application No. 63/641,263, filed May 1, 2024, and U.S. Provisional Application No. 63/677,856, filed July 31, 2024, the contents of each of which are incorporated herein by reference in their entirety. FIELD OF THE INVENTION [0002] The present invention relates to rodent (e.g., mouse or rat) models of disease, wherein the rodent is genetically engineered to express at least an antigen presenting portion of a classical human leukocyte antigen (HLA), and wherein the rodent comprises, in its periphery, human T cells genetically modified to express at least a recombinant human T cell receptor (TCR) variable domain that binds an antigen presented in the context of the antigen presenting portion of the HLA. The invention further relates to methods of making said rodent models of disease and methods of using the same, e.g., for determining the pathogenicity of an antigen, for identifying a therapeutic candidate for the treatment of a disorder associated with an HLA-peptide-TCR interaction, etc. SEQUENCE LISTING [0003] A Sequence Listing in XML format entitled “11767WO01.xml,” which was created March 18, 2025, and is 18 Kb, is incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION [0004] In the adaptive cellular immune response, pathogenic antigens are recognized in the context of major histocompatibility complex (MHC) by T cell receptor (TCR) expressed on the cell surface of T lymphocytes. The MHC (referred to as human leukocyte antigen in humans) presents pathogenic antigens as peptide fragments. Specific interaction of a TCR with an antigen-MHC complex leads to activation of the T cell, and its effector functions. [0005] Not all antigens are pathogenic. For example, self-antigen or food-based antigens typically will not provoke T cell activation due to tolerance mechanisms. However, in some diseases (e.g., autoimmune diseases, etc.) peptides derived from self-proteins or exogenously introduced proteins (e.g., gluten) become the target of the cellular component of the immune system, which results in destruction of healthy cells presenting such peptides. There has been significant advancement in recognizing antigens as well as the specific MHC alleles that present these antigens that are clinically significant. However, there remains a need for non-human models of human diseases and/or disorders associated pathogenic MHC-antigen-TCR interactions, e.g., for developing therapeutic candidates to treat the same, as well as model systems for determining the T cell-dependent pathogenicity of antigens. SUMMARY OF THE INVENTION [0006] Provided herein are rodents that are genetically modified to support the engraftment of human T cells, that comprise genetically modified human T cells, and that are useful as models of disease, for identifying treatments thereof, and for determining the pathogenicity of antigens. [0007] In certain embodiments, a genetically modified rodent as described herein comprises: (a) in its genome, a first recombinant nucleic acid, wherein the first recombinant nucleic acid encodes at least an antigen presenting portion of a classical human leukocyte antigen (HLA) molecule, wherein the antigen presenting portion of the classical HLA molecule comprises α1, α2, and α3 domains of a classical HLA class I molecule; or α1, α2, β1, and β2 domains of a classical HLA class II molecule; and (b) in its periphery, a human T cell, wherein the human T cell is genetically modified to express a second recombinant nucleic acid that encodes a recombinant human T cell receptor (TCR) variable domain, wherein the human T cell expresses the recombinant human TCR variable domain on its cell surface, and wherein the recombinant human TCR variable domain binds an antigen presented in the context of the antigen presenting portion of the classical HLA molecule. In some embodiments, the first recombinant nucleic acid is at an endogenous classical MHC locus and/or replaces an endogenous classical MHC gene or portion thereof. In some embodiments, the rodent is homozygous for a replacement of the endogenous classical MHC gene or portion thereof with the first recombinant nucleic acid. [0008] In further embodiments of the genetically modified rodent as described herein, the second recombinant nucleic acid is operably linked to a non-human promoter (e.g., EF1α promoter, spleen focus-forming virus (SFFV) promoter, etc.) that controls expression of the recombinant human TCR variable domain and/or a non-human regulatory element (e.g., Woodchuck posttranscriptional regulatory element (WPRE)) that enhances expression of the recombinant human TCR variable domain. In some embodiments, the second recombinant nucleic acid is episomal, randomly integrated, or replaces an endogenous TCR sequence at an endogenous TCR locus. In some embodiments, the recombinant human TCR variable domain is expressed fused to a linker sequence (e.g., a furin-cleavable linker). In some embodiments, the human T cell comprises a viral nucleic acid (e.g., viral nucleic acid encoding a 2A peptide (e.g., a T2A peptide, a P2A peptide, a F2A peptide, etc.), an adeno-associated viral nucleic acid (e.g., an AAV ITR), etc.). [0009] In some embodiments, the genetically modified rodent does not comprise, in its periphery: (i) mature rodent B cells, (ii) mature rodent T cells, and/or (iii) rodent NK cells. [0010] In some embodiments, the genetically modified rodent further comprises, in its genome: (i) a knockout mutation of an endogenous Rag gene, and/or (ii) a knockout mutation of an endogenous interleukin-2 receptor (Il2r) gene. In some embodiments, the endogenous Rag gene comprises an endogenous Rag2 gene. In further embodiments, the rodent is homozygous for the knockout mutation of the endogenous Rag, optionally endogenous Rag2, gene. In some embodiments, the endogenous IL-2r gene comprises an endogenous Il2rγ gene. In further embodiments, the genetically modified rodent is homozygous for the knockout mutation of the endogenous Il2r, optionally endogenous Il2rγ, gene. [0011] In some embodiments, the genetically modified rodent further comprises, in its genome: (i) a human or humanized interleukin-15 (IL15) gene, and/or (ii) a human or humanized Signal Regulatory Protein Alpha (SIRPA) gene. In some embodiments, the human or humanized IL15 gene is at an endogenous IL15 locus and/or replaces an endogenous IL15 gene. In some embodiments, the genetically modified rodent is homozygous for a replacement of the endogenous IL15 gene with the human or humanized IL15 gene. In some embodiments, the human or humanized SIRPA gene is at an endogenous sirpa locus and/or replaces an endogenous sirpa gene. In some embodiments, the genetically modified rodent is homozygous for a replacement of the endogenous sirpa gene with the human or humanized SIRPA gene. [0012] In further embodiments of the genetically modified rodent as described herein, the human T cell is an activated effector T cell. In some embodiments, the genetically modified rodent exhibits one or more symptoms of a disease associated with the classical HLA molecule, the antigen or the combination of the classical HLA molecule and the antigen. [0013] In further embodiments of the genetically modified rodent as described herein, the first recombinant nucleic acid encodes at least an antigen presenting portion of an HLA-B molecule, an HLA-DR1 molecule, an HLA-DR2 molecule, an HLA-DR3 molecule, an HLA-DR4 molecule, an HLA-DR13 molecule, an HLA-DR15 molecule, an HLA-DQ2 molecule, an HLA- DQ4 molecule, an HLA-DQ8 molecule, an HLA-DQ9 molecule, or a combination thereof. [0014] In further embodiments of the genetically modified rodent as described herein, the first recombinant nucleic acid encodes at least an antigen presenting portion of an HLA molecule that is associated with a disease as set forth in Table 1, wherein the antigen comprises an antigen, or a portion thereof, that is associated with the disease as set forth in Table 1, and wherein the genetically modified rodent exhibits one or more characteristics of the disease. [0015] In further embodiments of the genetically modified rodent as described herein, the first recombinant nucleic acid encodes at least an antigen presenting portion of an HLA-DQ2.5 molecule, wherein the antigen is gliadin, or a portion thereof, and wherein the genetically modified rodent exhibits one or more characteristics of celiac disease (e.g., wherein the genetically modified rodent comprises an activated effector T cell that specifically binds gliadin, or the portion thereof, presented in the context of the antigen presenting portion of HLA-DQ2.5). In some embodiments, the activated effector T cell expresses an activation-induced marker (AIM), e.g., Ki67, IFNG, GZMB, 4-1BB, HLA-DR, ICOS, PD1, CD39 and/or CCL5. In some embodiments, the activated effector T cell is found in the blood, spleen and/or small intestine of the genetically modified rodent. [0016] In certain embodiments, the genetically modified rodent as described herein is a genetically modified mouse. In some embodiments, the genetically modified mouse comprises: (a) in its genome, (i) the first recombinant nucleic acid, wherein the first recombinant nucleic acid encodes at least the α1, α2, β1, and β2 domains of a classical HLA-DQ2.5 class II molecule, (ii) a human or humanized SIRPA gene, (iii) a homozygous knockout mutation of an endogenous Rag2 gene, and (iv) a homozygous knockout mutation of an endogenous Il2rγ gene; and (b) in its periphery, the human T cell, wherein the human T cell expresses the recombinant human TCR variable domain on its cell surface, wherein the recombinant human TCR variable domain recognizes gliadin presented in the context of the α1, α2, β1, and β2 domains of the classical HLA-DQ2.5 class II molecule. In some embodiments, the genetically modified mouse comprises: (a) in its genome, (i) the first recombinant nucleic acid, wherein the first recombinant nucleic acid encodes at least the α1, α2, β1, and β2 domains of a classical HLA-DQ2.5 class II molecule, (ii) a human or humanized IL15 gene, (iii) a human or humanized SIRPA gene, (iv) a homozygous knockout mutation of an endogenous Rag2 gene, and (v) a homozygous knockout mutation of an endogenous Il2rγ gene; and (b) in its periphery, the human T cell, wherein the human T cell expresses the recombinant human TCR variable domain on its cell surface, wherein the recombinant human TCR variable domain recognizes gliadin presented in the context of the α1, α2, β1, and β2 domains of the classical HLA-DQ2.5 class II molecule. [0017] In further embodiments of the genetically modified rodent as described herein, the recombinant human TCR variable domain comprises: (i) a TCR α variable domain encoded by a TRAV9-2 gene segment and comprising a complementary determining region (CDR) 3 that comprises an amino acid sequence of ALSDHYSSGSARQLT (SEQ ID NO: 10), and (ii) a TCR β variable domain encoded by a TRBV7-2 gene segment and comprising a CDR3 that comprises an amino acid sequence of ASSTAVLAGGPQY (SEQ ID NO: 14). In some embodiments, the recombinant human TCR variable domain comprises: (i) a TCR α variable domain encoded by a TRAV9-2 gene segment and comprising a an amino acid sequence as set forth in SEQ ID NO: 11, and (ii) a TCR β variable domain encoded by a TRBV7-2 gene segment and comprising an amino acid sequence as set forth in SEQ ID NO: 15. [0018] In further embodiments of the genetically modified rodent as described herein, the human T cell (a) exhibits an effector memory phenotype (e.g., wherein the human T cell has one or more of the following phenotypes: CD45RO+, CD62L-, CCR7lo, CD45RA-), (b) is found in the blood, spleen, or small intestine, and/or (c) expresses an AIM, e.g., Ki67, IFNG, GZMB, 4-1BB, HLA-DR, ICOS, PD1, CD39 and/or CCL5. [0019] In further embodiments, the genetically modified rodent as described herein further comprises an antigen that binds to the antigen presenting portion of the classical HLA molecule. In some embodiments, the recombinant human TCR variable domain binds the antigen presented in the context of the antigen presenting portion of the classical HLA. In some embodiments, the antigen is a gliadin peptide. [0020] In certain embodiments, described herein is a method of making a rodent model of disease. In some embodiments, the method comprises administering an antigen to the genetically modified rodent as described above, wherein the antigen is recognized by the recombinant TCR variable domain expressed by the adoptively transferred human T cell genetically modified to express the recombinant TCR variable domain. In further embodiments, the method comprises determining, after administering the antigen, the absence or presence of activated human T cells in the genetically modified rodent, wherein the presence of activated human T cells in the genetically modified rodent indicates that the rodent is modeling the disease. [0021] In further embodiments of the method of making as described herein, the genetically modified rodent is a genetically modified mouse, wherein the genetically modified mouse comprises: (a) in its genome, (i) the first recombinant nucleic acid, wherein the first recombinant nucleic acid encodes at least the α1, α2, β1, and β2 domains of a classical HLA-DQ2.5 class II molecule, (ii) a human or humanized SIRPA gene, (iii) a homozygous knockout mutation of an endogenous Rag2 gene, and (iv) a homozygous knockout mutation of an endogenous Il2rγ gene; and (b) in its periphery, the human T cell, wherein the human T cell expresses the recombinant human TCR variable domain on its cell surface, wherein the recombinant human TCR variable domain recognizes gliadin presented in the context of the α1, α2, β1, and β2 domains of the classical HLA-DQ2.5 class II molecule. In some embodiments, the genetically modified mouse comprises: (a) in its genome, (i) the first recombinant nucleic acid, wherein the first recombinant nucleic acid encodes at least the α1, α2, β1, and β2 domains of a classical HLA-DQ2.5 class II molecule, (ii) a human or humanized IL15 gene, (iii) a human or humanized SIRPA gene, (iv) a homozygous knockout mutation of an endogenous Rag2 gene, and (v) a homozygous knockout mutation of an endogenous Il2rγ gene; and (b) in its periphery, the human T cell, wherein the human T cell expresses the recombinant human TCR variable domain on its cell surface, wherein the recombinant human TCR variable domain recognizes gliadin presented in the context of the α1, α2, β1, and β2 domains of the classical HLA-DQ2.5 class II molecule. In some embodiments, administering comprises oral gavage with a gliadin peptide. [0022] In further embodiments of the method of making as described herein, determining the absence or presence of activated human T cells in the genetically modified rodent comprises determining the phenotype of human T cells in a sample isolated from the genetically modified rodent, wherein the sample is selected from the group consisting of blood, spleen, and small intestine. In some embodiments, determining the absence or presence of activated human T cells comprises evaluating the activation state of a human T cell isolated from a sample isolated from the genetically modified rodent. In some embodiments, evaluating the activation state of the human T cell comprises determining the expression level of a T cell AIM, optionally wherein the AIM is selected from the group consisting of Ki67, IFNG, GZMB, 4-1BB, HLA-DR, ICOS, PD1, CD39, CCL5, and any combination thereof. [0023] In certain embodiments, the present invention comprises a method of using the genetically modified rodents as described herein. In some embodiments, provided herein is a method of identifying a therapeutic candidate for the treatment of a disorder associated with a pathogenic MHC-peptide-TCR interaction. In some embodiments, the method comprises introducing, into a genetically modified rodent as described herein, an antigen that binds the recombinant TCR variable domain when presented in the context of the antigen presenting portion of the classical HLA molecule, wherein the antigen bound to the antigen presenting portion of the classical HLA molecule activates the human T cell into a human effector T cell, administering the therapeutic candidate to the genetically modified rodent, and determining whether the therapeutic candidate reduces, prevents, or inhibits activation of the human T cell into a human effector T cell, wherein a reduction, prevention, or inhibition of activation of the human T cell into a human effector T cell identifies the therapeutic candidate as capable of treating the disorder associated with the pathogenic MHC-peptide-TCR interaction. In some embodiments, introducing the antigen and administering the therapeutic candidate occurs simultaneously. In some embodiments, administering the therapeutic candidate occurs after introducing the antigen. In some embodiments, administering the therapeutic candidate occurs before introducing the antigen. [0024] In further embodiments of the method of use as described herein, the therapeutic candidate comprises a protein that specifically binds to (i) the antigen presented in the context of the antigen presenting portion of the classical HLA molecule, (ii) the recombinant human TCR variable domain, or (iii) both the antigen presented in the context of the antigen presenting portion of the classical HLA molecule and the recombinant human TCR variable domain. In some embodiments, the protein comprises an antigen binding protein (e.g., an antibody) or binding fragment thereof. [0025] In further embodiments of the method of use as described herein, the genetically modified rodent is a genetically modified mouse, wherein the genetically modified mouse comprises: (a) in its genome, (i) the first recombinant nucleic acid, wherein the first recombinant nucleic acid encodes at least the α1, α2, β1, and β2 domains of a classical HLA-DQ2.5 class II molecule, (ii) a human or humanized SIRPA gene, (iii) a homozygous knockout mutation of an endogenous Rag2 gene, and (iv) a homozygous knockout mutation of an endogenous Il2rγ gene; and (b) in its periphery, the human T cell, wherein the human T cell expresses the recombinant human TCR variable domain on its cell surface, wherein the recombinant human TCR variable domain recognizes gliadin presented in the context of the α1, α2, β1, and β2 domains of the classical HLA-DQ2.5 class II molecule. In some embodiments, the genetically modified mouse comprises: (a) in its genome, (i) the first recombinant nucleic acid, wherein the first recombinant nucleic acid encodes at least the α1, α2, β1, and β2 domains of a classical HLA-DQ2.5 class II molecule, (ii) a human or humanized IL15 gene, (iii) a human or humanized SIRPA gene, (iv) a homozygous knockout mutation of an endogenous Rag2 gene, and (v) a homozygous knockout mutation of an endogenous Il2rγ gene; and (b) in its periphery, the human T cell, wherein the human T cell expresses the recombinant human TCR variable domain on its cell surface, wherein the recombinant human TCR variable domain recognizes gliadin presented in the context of the α1, α2, β1, and β2 domains of the classical HLA-DQ2.5 class II molecule. In some embodiments, administering comprises oral gavage with a gliadin peptide. [0026] In further embodiments of the method of use as described herein, the therapeutic candidate binds (i) gliadin, or a portion thereof, presented in the context of HLA-DQ2.5 and/or (ii) the recombinant human TCR variable domain that binds gliadin, or a portion thereof, presented in the context of the antigen presenting portion of HLA-DQ2.5. [0027] Also described herein are methods of making a rodent, wherein the method comprises introducing, into a genetically modified rodent, a genetically modified human T cell, wherein the genetically modified human T cell expresses a recombinant nucleic acid that encodes a recombinant human TCR variable domain that binds an antigen presented in the context of an antigen presenting portion of a classical HLA molecule, and wherein the genetically modified rodent expresses at least the antigen presenting portion of the classical HLA molecule. In some methods of making the rodent, the genetically modified rodent comprises, in its genome, a recombinant nucleic acid that encodes the antigen presenting portion of the classical HLA molecule, wherein the antigen presenting portion of the classical HLA molecule comprises α1, α2, and α3 domains of a classical HLA class I molecule; or α1, α2, β1, and β2 domains of a classical HLA class II molecule and/or wherein the recombinant nucleic acid that encodes the antigen presenting portion of the classical HLA molecule is at an endogenous classical MHC locus and/or replaces an endogenous classical MHC gene or portion thereof. In some embodiments, the rodent is homozygous for a replacement of the endogenous classical MHC gene or portion thereof with the first recombinant nucleic acid. [0028] In some embodiments, the genetically modified human T cell is introduced into the genetically modified rodent by intravenous injection. [0029] In some method of making embodiments, the recombinant nucleic acid that encodes the recombinant human TCR variable domain that binds the antigen presented in the context of an antigen presenting portion of the classical HLA molecule: is operably linked to a non-human promoter (e.g., EF1α promoter, spleen focus-forming virus (SFFV) promoter, etc.) that controls expression of the recombinant human TCR variable domain and/or a non-human regulatory element (e.g., Woodchuck posttranscriptional regulatory element (WPRE)) that enhances expression of the recombinant human TCR variable domain; comprises a non-human nucleic acid, e.g., a viral nucleic acid (e.g., viral nucleic acid encoding a 2A peptide (e.g., a T2A peptide, a P2A peptide, a F2A peptide, etc.), an adeno-associated viral nucleic acid (e.g., an AAV ITR), etc., and/or is episomal, randomly integrated, or replaces an endogenous TCR sequence at an endogenous TCR locus. [0030] In some embodiments of making a rodent as described herein, the method comprises modifying the genome of a rodent to comprise the recombinant nucleic acid that encodes the antigen presenting portion of the classical HLA molecule, and optionally one or more knockout mutations that provide for an immunodeficient background and/or one or more humanizations in which an exogenous nucleic acid sequence is inserted into the genome of the rodent to form a humanized gene that encodes a human or humanized polypeptide that promotes the development and/or function of transplanted human cells. In certain embodiments, the method of making the genetically modified rodent as described herein comprises: (a) modifying the genome of a rodent to comprise the recombinant nucleic acid encoding at least the antigen presenting portion of a classical HLA molecule and one or more additional genetic modification selected from the group consisting of: (i) a human or humanized IL15 gene, (ii) a human or humanized SIRPA gene, (iii) a homozygous knockout mutation of an endogenous Rag2 gene, and (iv) a homozygous knockout mutation of an endogenous Il2rγ gene; and (b) introducing into the genetically modified rodent the human T cell that expresses the second recombinant nucleic acid that encodes the recombinant human TCR variable domain that binds an antigen presented in the context of the antigen presenting portion of the classical HLA molecule. BRIEF DESCRIPTION OF THE DRAWINGS [0031] Figure 1 shows a schematic illustration, not to scale, of MHC class II I-E and I-A genes, showing knockout of the mouse locus using a hygromycin cassette in ES cells (MAID 5111), followed by introduction of a vector comprising humanized I-A β and I-A α (i.e., HLA- DQβ1*02/H-2Aβ and HLA-DQα1*05/H-2Aα chimeras, respectively) that replaces the hygromycin cassette with genes encoding chimeric human/mouse HLA-DQ2.5/H2-A. In the diagram, unless indicated otherwise (e.g., loxP site, etc.), the empty boxes or triangles are sequences of the human exons, the double lines are sequences of the human introns, the filled boxes or triangles are sequences of the mouse exons, and single lines are sequences of mouse introns. Location of junctional sequences are indicated below each targeting vector diagram and presented in Table 2 and the Sequence Listing. Mice comprising MHC class II I-E and I-A loci modified according to Figure 1 and expressing the HLA-DQβ1*02/H-2Aβ and HLA- DQα1*05/H-2Aα proteins may be referred to herein as “HLA-DQ2.5/H2-A mice,” “HLA- DQ2.5/H-2A-expressing mice” and the like. [0032] Figures 2A-2C provide a schematic (not to scale) for engineering of α1-gliadin-specific T cells. Figure 2A depicts a schematic of sgRNAs targeting the TRAC and TRBC locus for CRISPR/CAS9-mediated knockout (KO) of the endogenous TCR (Step 1) and of the gliadin TCR construct being introduced into TCR KO cells by lentiviral transduction (Step 2). Figure 2B shows CD3 (y-axis) and TCRαβ expression (x-axis) on total human wildtype T cells (“WT”), T cells after CRISPR/Cas9 KO of the endogenous TCR (“TCR KO”) and TCR KO T cells after lentiviral transduction of the gliadin TCR construct (“Engineered TCR”). Figure 2C depicts IFNγ production of engineered α1-gliadin-specific T cells (black bars) or untransduced TCR KO T cells (gray bars) as assessed by flow cytometry without stimulation (“Unstim”; negative control) or after in vitro restimulation with the cognate peptide α1-gliadin (“α1 pep”), non- cognate peptide α2-gliadin (“α2 pep”) or a phorbol 12-myristate 13-acetate and ionomycin cocktail (“PMA + IONO”; positive control) gated on CD4 cells (left panel) or CD8 cells (right panel). [0033] Figures 3A-3C demonstrate that α1-gliadin TCR CD4+ T cells transferred into HLA-DQ2.5/H2-A mice (also knocked-in for human IL15 and human SIRPA on a Rag2-/-/Il2rg-/- background) (see Figure 1) are activated after oral gavage with a synthetic peptide containing the α1-gliadin sequence. Figures 3A-3C depict the percentage of CD4+ T cells expressing Ki67 (left panels), Granzyme B (middle panels) and of various phenotypes based on CD45RO and CD62L expression (right panels; “EMRA” = “terminal differentiated effector memory”, “EM” = “effector memory”, “CM” = “central memory”, and “Naïve” = “antigen-inexperienced”) in the blood (Figure 3A), the spleen (Figure 3B) and small intestine (Figure 3C) of HLA-DQ2.5/H2-A mice administered PBS vehicle or 5 mg of α1/α2 gliadin-derived peptide as evaluated by flow cytometry. [0034] Figures 4A-4C demonstrate that α1-gliadin CD8+ TCR T cells transferred into HLA-DQ2.5/H2-A mice (also knocked-in for human IL15 and human SIRPA on a Rag2-/-/Il2rg-/- background) (see Figure 1) are activated after oral gavage with a synthetic peptide containing the α1-gliadin sequence. Figures 4A-4C depict the percentage of CD8+ T cells expressing Ki67 (left panels), Granzyme B (middle panels) and various phenotypes based on CD45RO and CD62L expression (right panels; “EMRA” = “terminal differentiated effector memory”, “EM” = “effector memory”, “CM” = “central memory”, and “Naïve” = “antigen-inexperienced”) in the blood (Figure 4A), the spleen (Figure 4B) and small intestine (Figure 4C) of HLA-DQ2.5/H2- A mice administered PBS vehicle or 5 mg of α1/α2 gliadin-derived peptide as evaluated by flow cytometry. [0035] Figure 5A depicts a gene expression analysis (IFNγ, Granzyme B, and CCL5) of the small intestine of HLA-DQ2.5/H2-A mice administered PBS vehicle or 5 mg of α1/α2 gliadin- derived peptide as determined by TaqMan PCR. Figure 5B shows serum expression analysis (IFNγ, IL-2, and TNF-α) of the small intestine of HLA-DQ2.5/H2-A mice administered PBS vehicle or 5 mg of α1/α2 gliadin-derived peptide as determined by immunoassay. DETAILED DESCRIPTION OF THE INVENTION [0036] The present invention provides genetically modified rodents that (a) express a human or humanized MHC molecule, e.g., a human leukocyte antigen (HLA) molecule or an MHC molecule, e.g., a chimeric human/rodent MHC molecule, comprising at least the antigen presenting portion of an HLA molecule, and (b) comprise a human T cell, e.g., in the periphery, that is genetically modified to express a recombinant human TCR variable domain that binds an antigen presented in the context of the antigen presenting portion of the human or humanized MHC molecule. [0037] In one embodiment, the rodent is selected from a mouse, a rat, and a hamster. In one embodiment, the rodent is selected from the superfamily Muroidea. In one embodiment, the genetically modified rodent is from a family selected from Calomyscidae (e.g., mouse-like hamsters), Cricetidae (e.g., hamster, New World rats and mice, voles), Muridae (true mice and rats, gerbils, spiny mice, crested rats), Nesomyidae (climbing mice, rock mice, with-tailed rats, Malagasy rats and mice), Platacanthomyidae (e.g., spiny dormice), and Spalacidae (e.g., mole rates, bamboo rats, and zokors). In a specific embodiment, the genetically modified rodent is selected from a true mouse or rat (family Muridae), a gerbil, a spiny mouse, and a crested rat. In a specific embodiment, the rodent is selected from a mouse and a rat. In one embodiment, the rodent is a mouse. [0038] In a specific embodiment, rodent is a mouse of a C57BL strain selected from C57BL/A, C57BL/An, C57BL/GrFa, C57BL/KaLwN, C57BL/6, C57BL/6J, C57BL/6ByJ, C57BL/6NJ, C57BL/10, C57BL/10ScSn, C57BL/10Cr, and C57BL/Ola. In another embodiment, the mouse is a 129 strain selected from the group consisting of a strain that is 129P1, 129P2, 129P3, 129X1, 129S1 (e.g., 129S1/SV, 129S1/SvIm), 129S2, 129S4, 129S5, 129S9/SvEvH, 129S6 (129/SvEvTac), 129S7, 129S8, 129T1, 129T2 (see, e.g., Festing et al. (1999) Revised nomenclature for strain 129 mice, Mammalian Genome 10:836, see also, Auerbach et al (2000) Establishment and Chimera Analysis of 129/SvEv- and C57BL/6-Derived Mouse Embryonic Stem Cell Lines). In a specific embodiment, the genetically modified mouse is a mix of an aforementioned 129 strain and an aforementioned C57BL/6 strain. In another specific embodiment, the mouse is a mix of aforementioned 129 strains, or a mix of aforementioned BL/6 strains. In a specific embodiment, the 129 strain of the mix is a 129S6 (129/SvEvTac) strain. In another embodiment, the mouse is a BALB strain, e.g., BALB/c strain. In yet another embodiment, the mouse is a mix of a BALB strain and another aforementioned strain. [0039] In one embodiment, the rodent is a rat. In one embodiment, the rat is selected from a Wistar rat, an LEA strain, a Sprague Dawley strain, a Fischer strain, F344, F6, and Dark Agouti. In one embodiment, the rat strain is a mix of two or more strains selected from the group consisting of Wistar, LEA, Sprague Dawley, Fischer, F344, F6, and Dark Agouti. [0040] Singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to “a method” includes one or more methods, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure. Moreover, by way of further example, “a recombinant nucleic acid” includes one or more recombinant nucleic acids. [0041] The terms “major histocompatibility complex,” and “MHC” encompass the terms “human leukocyte antigen” or “HLA” (the latter two of which are generally reserved for human MHC molecules), naturally occurring MHC molecules, individual chains of MHC molecules (e.g., MHC class I α (heavy) chain, MHC class II α chain, and MHC class II β chain), individual subunits of such chains of MHC molecules (e.g., α1, α2, and/or α3 subunits of MHC class I α chain, α1-α2 subunits of MHC class II α chain, β1- β2 subunits of MHC class II β chain) as well as portions (e.g., the antigen presenting portion, e.g., the peptide-binding portion, e.g., the peptide binding groove), mutants and various derivatives thereof (including fusions proteins), wherein such portion, mutants and derivatives retain the ability to display an antigenic peptide for recognition by a T cell receptor (TCR), e.g., an antigen-specific TCR. Conventional identifications of particular MHC variants are used herein. The terms “molecule” and “polypeptide” in reference to MHC or HLA may be used interchangeably herein, and may refer to (a) associated complexes, e.g., an MHC class II complex comprising α and β chains, (b) individual MHC/HLA chains, e.g., an MHC class II β chain, and/or (c) fragments thereof, e.g., subunits or domains of the individual chains, e.g., the β1 subunit of the β chain of an MHC class II complex. As used herein, “a” nucleic acid encoding an MHC, or a portion thereof, encompasses one or more nucleic acids encoding one or more subunits of an MHC, or portions thereof. For example, a nucleic acid encoding the antigen presenting portion of an MHC class II molecule, e.g., the antigen presenting portion of an MHC class II polypeptide complex comprising α and β chains, encompasses (i) a single nucleic acid encoding the antigen presenting portions of both the α and β chains, and (ii) more than one nucleic acid encoding the antigen presenting portions of the α and β chains, individually, e.g., a first nucleic acid encoding the antigen presenting portion of an MHC class II α chain, e.g., the α1 and α2 domains, and a second nucleic acid encoding the antigen presenting portion of an MHC class II β chain, e.g., the β1 and β2 domains. [0042] MHC molecules are encoded by multiple loci that are found as a linked cluster of genes that spans about 4 Mb. In mice, the MHC genes are found on chromosome 17, and for historical reasons are referred to as the histocompatibility 2 (H-2) genes. In humans, the genes are found on chromosome 6 and are called human leukocyte antigen (HLA) genes. The loci in mice and humans are polygenic; they include three highly polymorphic classes of MHC genes (class I, II and III) that exhibit similar organization in human and murine genomes. [0043] As used herein the terms “classical MHC” or “classical HLA” refer to class I or class II MHC, e.g., HLA, molecules and/or genes encoding the same. In humans, the classical HLA class I genes are termed HLA-A, HLA-B, and HLA-C, whereas in mice they are the termed H2-D, H2-L and H2-K. In humans, the classical HLA class II genes are termed HLA-DP, HLA-DQ, and HLA-DR, whereas in mice they are H-2A and H-2E (often abbreviated as I-A and I-E, respectively). [0044] An MHC class I molecule is an integral membrane protein comprising a glycoprotein heavy chain, also referred to herein as the α chain, which has three extracellular domains (i.e., α1, α2 and α3) and two intracellular domains (i.e., a transmembrane domain (TM) and a cytoplasmic domain (CYT)). The heavy chain is noncovalently associated with a soluble subunit called β2 microglobulin (β2m or β2M). An MHC class II molecule or MHC class II protein is a heterodimeric integral membrane protein comprising one α chain and one β chain in noncovalent association. The α chain has two extracellular domains (α1 and α2), and two intracellular domains (a TM domain and a CYT domain). The β chain contains two extracellular domains (β1 and β2), and two intracellular domains (a TM domain and CYT domain). [0045] MHC class I and II molecules comprise an antigen presenting portion, e.g., a peptide binding groove, peptide-binding cleft, etc. “Antigen presenting portion”, as used herein, refers to the minimum amino acid sequence and/or structure of an MHC required for antigen binding and presentation. An MHC class I molecule comprises an antigen presenting portion, e.g., a peptide binding groove, formed by the α1 and α2 domains of the heavy α chain that can stow a peptide of around 8-10 amino acids. Despite the fact that both classes of MHC bind a core of about 9 amino acids (e.g., 5 to 17 amino acids) within peptides, the open-ended nature of MHC class II antigen presenting portion (e.g., the peptide binding groove; i.e., the α1 domain of a class II MHC α polypeptide in association with the β1 domain of a class II MHC β polypeptide) allows for a wider range of peptide lengths. Peptides binding MHC class II usually vary between 13 and 17 amino acids in length, though shorter or longer lengths are not uncommon. As a result, peptides may shift within the MHC class II antigen presenting portion, e.g., peptide binding groove, changing which 9-mer sits directly within the groove at any given time. [0046] The terms "antigen", “epitope” and “antigenic determinant” as used interchangeably herein encompass any agent (e.g., protein, peptide, polysaccharide, glycoprotein, glycolipid, nucleotide, portions thereof, or combinations thereof) that, when introduced into an immunocompetent host is recognized by the immune system of the host and elicits an immune response by the host. The T-cell receptor (TCR) recognizes a peptide presented in the context of a major histocompatibility complex (MHC) as part of an immunological synapse. The peptide-MHC (pMHC) complex is recognized by TCR, with the peptide (antigenic determinant) and the TCR idiotype providing the specificity of the interaction. Accordingly, the term “antigen” encompasses peptides presented in the context of MHCs, e.g., peptide-MHC complexes, e.g., pMHC complexes. The terms "peptide," "antigenic determinant," "epitopes," etc., encompass not only those presented naturally by antigen-presenting cells (APCs), but may be any desired peptide so long as it is recognized by a T cell when presented appropriately to the T cell. For example, a peptide having an artificially prepared amino acid sequence may also be used as the epitope. [0047] T cells bind antigens presented by an MHC through a T cell receptor (TCR) complex on the surface of the T cell. T cell receptors are heterodimeric structures composed of two types of chains: an α (alpha) and β (beta) chain, or a γ (gamma) and δ (delta) chain. The α chain is encoded by the nucleic acid sequence located within the α locus on human chromosome 14, which also encompasses the entire δ locus, and the β chain is encoded by the nucleic acid sequence located within the β locus on human chromosome 7. The majority of T cells have an αβ TCR; while a minority of T cells bear a γδ TCR. [0048] T-cell receptor α and β polypeptides (and similarly γ and δ polypeptides) are linked to each other via a disulfide bond. Each of the two polypeptides that make up the TCR contains an extracellular domain comprising constant and variable regions, a transmembrane domain, and a cytoplasmic tail (the transmembrane domain and the cytoplasmic tail also being a part of the constant region). The variable region of the TCR determines its antigen specificity, and similar to immunoglobulins, comprises 3 complementary determining regions (CDRs), e.g., CDR1, CDR2, and CDR3. Also similar to immunoglobulin genes, T cell receptor variable gene loci (e.g., TCRα and TCRβ loci) contain a number of unrearranged V(D)J segments (variable (V), joining (J), and in TCRβ and δ, diversity (D) segments). During T cell development in the thymus, TCRα variable gene locus undergoes rearrangement, such that the resultant TCR α variable domain is encoded by a specific combination of VJ segments (Vα/Jα sequence); and TCRβ variable gene locus undergoes rearrangement, such that the resultant TCR β variable domain is encoded by a specific combination of VDJ segments (Vβ/Dβ/Jβ sequence). The TCR α and β variable domains, in particular the CDR1, CDR2, and CDR3 and more particularly the CDR3, provide the specificity with which the TCR binds an MHC. As used herein, “a” nucleic acid encoding a TCR, or a portion thereof, encompasses one or more nucleic acids encoding one or more subunits of a TCR, or a portion thereof. For example, a nucleic acid encoding a TCR variable domain, e.g., comprising non-covalently complexed variable domains of TCR α and TCR β subunits, encompasses (i) a single nucleic acid encoding both the TCR α variable domain and TCR β variable domain, and (ii) more than one nucleic acid encoding the TCR α variable domain and TCR β variable domain, individually, e.g., a first nucleic acid encoding a TCR α variable domain and a second nucleic acid encoding a TCR β variable domain. In one example herein, the TCR α and TCR β subunits of the gliadin-specific TCR are introduced on a single nucleic acid encoding both the TCR α variable domain and TCR β variable domain. [0049] The activation of a T cell following engagement with a peptide-MHC can be determined by identifying one or more activation-induced marker. An “activation-induced marker” or “AIM” is a marker that is expressed, or in which the expression is upregulated, after activation of a T cell. Well-known activation-induced markers for T cells include, but are not limited to, CD137/4-1BB, CD107, IFNγ, PD-1, CD40L, OX40, CD25, CD69, CD28, HLA-DR, CX3CR1, TIM3, LAG3, TIGIT, GZMB, CCL5, Ki67, CD39/ENTPD1, etc. In some embodiments, the T cell activation marker, e.g., the activation induced marker, comprises CD40L. CD40L may also be referred to as CD154. In some embodiments, the T cell activation marker, e.g., the activation induced marker, comprises tumor necrosis factor receptor superfamily, member 9 (TNFRSF9). TNFRSF9 is also referred to herein as CD137 and/or 4-1BB. Accordingly, CD137/4-1BB refers to the molecule known in the art as CD137, 4-1BB, TNFRSF9, and the like, and the phrases “CD137,” “4-1BB,” “CD137/4-1BB,” and “TNFRSF9” may be used interchangeably. CD137/4- 1BB is a transient T cell activation marker that is upregulated rapidly upon antigen-specific TCR engagement and remains expressed on cells for approximately 72 hours. In methods described herein, between 20-36 hours after exposure to an antigen appears to be the optimal time point for functional enrichment of CD137/4-1BB expression and detection. In some embodiments, the activation-induced marker comprises CD107. CD107 may also be referred to as CD107a or LAMP1. In some embodiments, the activation-induced marker comprises interferon gamma (IFNγ), which may also be referred to as gamma interferon, IFNG, IFG, etc. In some embodiments, the activation-induced marker comprises programmed cell death 1, which may also be referred to as PD-1, PD1, CD279, and HPD-1. In some embodiments, the activation-induced marker comprises TNF Receptor Superfamily member 4, which may also be referred to as OX40 and/or CD134. In some embodiments, the activation-induced marker comprises interleukin-2 receptor alpha, which may also be referred to as IL-2R, IL-2Rα, and/or CD25. In some embodiments, the activation-induced marker comprises CD69, which may also be referred to leukocyte surface antigen Leu-23 and/or MLR3. In some embodiments, the activation-induced marker comprises CD28, which may also be referred to Tp44 and/or T-cell specific surface glycoprotein. In some embodiments, the activation-induced marker comprises major histocompatibility complex class II DR, which may also be referred to as human leukocyte antigen class II DR and/or HLA-DR. In some embodiments, the activation-induced marker comprises C X C motif chemokine receptor (CX3CR1), which may also be referred to as IL-8 Receptor, IL-8Rα, and/or CDw128a. In some embodiments, the activation-induced marker comprises TIM3, which may also be referred to as Hepatitis A Virus Cellular Receptor 2, T cell Membrane Protein 3, and/or CD366. In some embodiments, the activation-induced marker comprises lymphocyte activation gene 3 (LAG3), which may also be referred to as CD223. In some embodiments, the activation-induced marker comprises T cell Immunoreceptor with Ig and ITIM Domains (TIGIT), which may also be referred to as V-Set and Immunoglobulin Domain Containing Protein 9 (VSIG9) and/or V-Set and/or Transmembrane Domain Containing 3 (VSTM3). In some embodiments, the activation-induced marker comprises granzyme B (GZMB), which may also be referred to as C11; HLP; CCPI; CGL1; CSPB; SECT; CGL-1; CSP-B; CTLA1; CTSGL1. In some embodiments, the activation-induced marker comprises chemokine (C-C motif) ligand 5 (CCL5), which may also be referred to as SISd; eoCP; SCYA5; RANTES; TCP228; D17S136E; SIS-delta. In some embodiments, the activation-induced marker comprises Ki-67 protein, which may also be referred to as Ki67; KIA; MIB-; MIB-1; PPP1R105. In some embodiments, the activation-induced marker comprises ectonucleoside triphosphate diphosphohydrolase 3, which may also be referred to as CD39 and/or ENTPD1. In some embodiments, the AIM comprises inducible T cell costimulatory, which may also be referred to herein as ICOS and/or CD278. [0050] The terms “protein” and “polypeptide” may be used interchangeably herein and encompass all kinds of naturally occurring and synthetic proteins, including protein fragments of all lengths, fusion proteins and modified proteins, including without limitation, glycoproteins, as well as all other types of modified proteins (e.g., proteins resulting from phosphorylation, acetylation, myristoylation, palmitoylation, glycosylation, oxidation, formylation, amidation, polyglutamylation, ADP-ribosylation, pegylation, biotinylation, etc.). Moreover, the terms “amino acid sequence”, “protein sequence”, and “polypeptide sequence” may be used interchangeably herein to refer to the arrangement and identity of monomeric amino acids in a polypeptide polymer. [0051] The present invention also encompasses polypeptides that comprise conservative amino acid substitutions in their amino acid sequence as compared to the polypeptides as described and/or exemplified herein. [0052] The term "conservative,” when used to describe a conservative amino acid substitution, includes substitution of an amino acid residue by another amino acid residue having a side chain R group with similar chemical properties (e.g., charge or hydrophobicity). Conservative amino acid substitutions may be achieved by modifying a nucleotide sequence so as to introduce a nucleotide change that will encode the conservative substitution. In general, a conservative amino acid substitution will not substantially change the functional properties of interest of a protein, for example, the ability of an MHC II to present a peptide of interest. Examples of groups of amino acids that have side chains with similar chemical properties include aliphatic side chains such as glycine, alanine, valine, leucine, and isoleucine; aliphatic-hydroxyl side chains such as serine and threonine; amide-containing side chains such as asparagine and glutamine; aromatic side chains such as phenylalanine, tyrosine, and tryptophan; basic side chains such as lysine, arginine, and histidine; acidic side chains such as aspartic acid and glutamic acid; and, sulfur-containing side chains such as cysteine and methionine. Conservative amino acids substitution groups include, for example, valine/leucine/isoleucine, phenylalanine/tyrosine, lysine/arginine, alanine/valine, glutamate/aspartate, and asparagine/glutamine. In some embodiments, a conservative amino acid substitution can be a substitution of any native residue in a protein with alanine, as used in, for example, alanine scanning mutagenesis. In some embodiments, a conservative substitution is made that has a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al. ((1992) Exhaustive Matching of the Entire Protein Sequence Database, Science 256:1443-45), hereby incorporated by reference. In some embodiments, the substitution is a moderately conservative substitution wherein the substitution has a nonnegative value in the PAM250 log-likelihood matrix. [0053] The terms “nucleic acid”, “nucleic acid molecule”, “nucleotide”, and “nucleotide molecule” may be used interchangeably herein and encompass both DNA, RNA, modified bases, or combinations of these bases unless specified otherwise. The terms also encompass fragments and/or portions of the same. Moreover, the terms “nucleic acid sequence” and “nucleotide sequence” may be used interchangeably herein to refer to arrangement and identity of monomeric nucleotides in a polynucleotide polymer. In some aspects, a nucleic as used herein may encode a polypeptide. “Encode” or “encoding” as used herein refers to a nucleotide sequence that may be transcribed and/or translated. For example, a DNA molecule encodes a polypeptide if an mRNA molecule transcribed therefrom can be translated into said polypeptide. One skilled in the art would understand that in addition to the nucleic acid residues encoding polypeptides as described and/or exemplified herein, due to the degeneracy of the genetic code, other nucleic acids may encode the polypeptide(s) of the invention. Therefore, in addition to the nucleotide sequences encoding polypeptides as described and/or exemplified herein, e.g., with conservative amino acid substitutions, nucleotide sequences that differ from those described and/or exemplified herein due to the degeneracy of the genetic code are also provided. [0054] The term "operably linked" refers to a juxtaposition wherein the components so described are in a relationship permitting them to function in their intended manner. As such, a nucleic acid sequence encoding a protein may be operably linked to regulatory sequences (e.g., promoter, enhancer, silencer sequence, etc.) so as to retain proper transcriptional regulation. In addition, various portions of the chimeric or humanized protein of the invention may be operably linked to retain proper folding, processing, targeting, expression, and other functional properties of the protein in the cell. Unless stated otherwise, various domains of the chimeric or humanized protein of the invention are operably linked to each other. Genetically Modified Rodents for Expressing an Antigen Presenting Portion of an HLA [0055] In various aspects, the invention provides a genetically modified rodent, e.g., rat or mouse, that comprises in its genome a nucleotide sequence, e.g., a recombinant nucleic acid, encoding a human, e.g., HLA, or humanized, e.g., chimeric human/rodent, MHC molecule. In various embodiments, the human or humanized MHC molecule is a classical MHC molecule. In various embodiments, the human or humanized MHC molecule comprises at least the antigen presenting portion of a classical HLA molecule. In some embodiments, antigen presenting portion of the classical HLA molecule comprises α1, α2, and α3 domains of a classical HLA class I molecule, or α1, α2, β1, and β2 domains of a classical HLA class II molecule. In various aspects, the nucleotide sequence, e.g., the recombinant nucleic acid, encoding the human or humanized MHC is present at an endogenous classical MHC locus and/or replaces an endogenous classical MHC gene or a portion thereof. In some embodiments, the genetically modified rodent is heterozygous for a replacement of the endogenous classical MHC gene or portion thereof with the nucleotide sequence, e.g., recombinant nucleic acid, encoding the human or humanized MHC molecule. [0056] The term “humanized,” “chimeric,” “human/non-human” and the like refers to a molecule (e.g., a nucleic acid, protein, etc.) that was non-human in origin and for which a portion has been replaced with a corresponding portion of a corresponding human molecule in such a manner that the modified (e.g., humanized, chimeric, human/non-human, etc.) molecule retains its biological function and/or maintains the structure that performs the retained biological function. A humanized molecule may be considered derived from a human molecule where the humanized molecule is encoded by a nucleotide comprising a nucleic acid sequence that encodes the human molecule (or a portion thereof). In contrast “human” and the like encompasses molecules having only a human origin, e.g., human nucleotides or protein comprising only human nucleotide and amino acid sequences respectively. The term “human(ized)” may be used to reflect that the human(ized) molecule may be (a) a human molecule or (b) a humanized molecule. [0057] The term “endogenous locus” or “endogenous gene” refers to a genetic locus found in a parent or reference organism prior to introduction of a disruption, deletion, replacement, alteration, or modification as described herein. In some embodiments, an endogenous locus has a sequence found in nature. In some embodiments, an endogenous locus is a wild-type locus. In some embodiments, an endogenous locus is an engineered locus. [0058] The term “replacement” in reference to gene replacement refers to placing exogenous genetic material at an endogenous genetic locus, thereby replacing all or a portion of the endogenous gene with an orthologous or homologous nucleic acid sequence. As demonstrated in the Examples below, the nucleotide sequence of the endogenous MHC II locus was replaced by a nucleotide sequence, e.g., recombinant nucleic acid, encoding a chimeric human/mouse MHC class II molecule, e.g., HLA-DQ2.5/H2-A. [0059] In specific embodiments, the genetically modified rodent comprises a nucleotide sequence, e.g., a recombinant nucleic acid, encoding at least an antigen presenting portion of an HLA class I molecule (e.g., an HLA-B molecule) or an HLA class II molecule, (e.g., an HLA- DR1 molecule, an HLA-DR2 molecule, an HLA-DR3 molecule, an HLA-DR4 molecule, an HLA-DR13 molecule, an HLA-DR15 molecule, an HLA-DQ2 molecule, an HLA-DQ4 molecule, an HLA-DQ8 molecule, an HLA-DQ9 molecule), or any combination thereof. HLA class I [0060] In various embodiments, the invention provides a genetically modified non-human animal (e.g., mouse, rat, rabbit, etc.) that comprises in its genome a nucleotide sequence encoding a human or humanized MHC class I polypeptide. The non-human animal may comprise in its genome a nucleotide sequence that encodes an MHC I polypeptide that is partially human and partially non-human, e.g., a non-human animal that expresses a chimeric human/non-human MHC I polypeptide. In one aspect, the non-human animal only expresses the human or humanized MHC I polypeptide, e.g., chimeric human/non-human MHC I polypeptide, and does not express an endogenous non-human MHC I protein from an endogenous MHC I locus. [0061] In one embodiment, the chimeric human/non-human MHC I polypeptide comprises in its human portion a peptide binding domain of a human MHC I polypeptide. In one aspect, the human portion of the chimeric polypeptide comprises an extracellular domain of a human MHC I. In this embodiment, the human portion of the chimeric polypeptide comprises an extracellular domain of an α chain of a human MHC I. In one embodiment, the human portion of the chimeric polypeptide comprises αl and α2 domains of a human MHC I. In another embodiment, the human portion of the chimeric polypeptide comprises αl, α2, and α3 domains of a human MHC I. [0062] The human or humanized MHC I polypeptide may be derived from a functional human HLA molecule encoded by any of HLA-A, HLA-B, or HLA-C loci. A list of commonly used HLA antigens is described in Shankarkumar et al. ((2004) The Human Leukocyte Antigen (HLA) System, Int. J. Hum. Genet. 4(2):91-103), incorporated herein by reference. Shankarkumar et al. also present a brief explanation of HLA nomenclature used in the art. Additional information regarding HLA nomenclature and various HLA alleles can be found in Holdsworth et al. (2009) The HLA dictionary 2008: a summary of HLA-A, -B, -C, - DRB1/3/4/5, and DQB1 alleles and their association with serologically defined HLA-A, -B, -C, - DR, and —DQ antigens, Tissue Antigens 73:95-170, and a recent update by Marsh et al. (2010) Nomenclature for factors of the HLA system, 2010, Tissue Antigens 75:291-455, both incorporated herein by reference. Thus, the human or humanized MHC I polypeptide may be derived from any functional human HLA class I molecules described therein. [0063] In one specific aspect, the human or humanized MHC I polypeptide is derived from human HLA-A. In a specific embodiment, the HLA-A polypeptide is an HLA-A2 polypeptide (e.g., and HLA-A2.1 polypeptide). In another specific aspect, the human or humanized MHC I polypeptide is derived from human MHC I selected from HLA-B and HLA-C. In one aspect, the human or humanized MHC I is derived from HLA-B, e.g., HLA-B27. [0064] In one aspect, the non-human portion of the chimeric human/non-human MHC I polypeptide comprises transmembrane and/or cytoplasmic domains of the non-human MHC I polypeptide. In one embodiment, the non-human animal is a mouse, and the non-human MHC I polypeptide is selected from H-2K, H-2D, and H-2L. In one embodiment, the non-human MHC I polypeptide is H-2K, e.g., H-2Kb. Although specific H-2K sequences are described in the Examples, any suitable H-2K sequences, e.g., polymorphic variants, conservative/non- conservative amino acid substitutions, etc., are encompassed herein. [0065] The non-human animal described herein may comprise in its genome a nucleotide sequence encoding a human or humanized MHC I polypeptide, e.g., chimeric human/non-human MHC I polypeptide, wherein the nucleotide sequence encoding such polypeptide is located at an endogenous non-human MHC I locus (e.g., H-2K locus). In one aspect, this results in a replacement of an endogenous MHC I gene or a portion thereof with a nucleotide sequence encoding a human or humanized MHC I polypeptide, e.g., a chimeric gene encoding a chimeric human/non-human MHC I polypeptide described herein. In one embodiment, the replacement comprises a replacement of an endogenous nucleotide sequence encoding a non-human MHC I peptide binding domain or a non-human MHC I extracellular domain with a human nucleotide sequence (e.g., HLA-A2 nucleotide sequence) encoding the same. In this embodiment, the replacement does not comprise a replacement of an MHC I sequence encoding transmembrane and/or cytoplasmic domains of a non-human MHC I polypeptide (e.g., H-2K polypeptide). Thus, the non-human animal contains chimeric human/non-human nucleotide sequence at an endogenous non-human MHC I locus, and expresses chimeric human/non-human MHC polypeptide from the endogenous non-human MHC I locus. [0066] A chimeric human/non-human polypeptide may be such that it comprises a human or a non-human leader (signal) sequence. In one embodiment, the chimeric polypeptide comprises a non-human leader sequence of an endogenous MHC I protein. In another embodiment, the chimeric polypeptide comprises a leader sequence of a human MHC I protein, e.g., HLA-A2 protein (for instance, HLA-A2.1 leader sequence). Thus, the nucleotide sequence encoding the chimeric MHC I polypeptide may be operably linked to a nucleotide sequence encoding a human MHC I leader sequence. [0067] A chimeric human/non-human MHC I polypeptide may comprise in its human portion a complete or substantially complete extracellular domain of a human MHC I polypeptide. Thus, the human portion may comprise at least 80%, preferably at least 85%, more preferably at least 90%, e.g., 95% or more of the amino acids encoding an extracellular domain of a human MHC I polypeptide (e.g., HLA-A2 polypeptide). In one example, substantially complete extracellular domain of the human MHC I polypeptide lacks a human MHC I leader sequence. In another example, the chimeric human/non-human MHC I polypeptide comprises a human MHC I leader sequence. [0068] Moreover, the chimeric MHC I polypeptide may be expressed under the control of endogenous non-human regulatory elements, e.g., rodent MHC I regulatory animals. Such arrangement will facilitate proper expression of the chimeric MHC I polypeptide in the non-human animal, e.g., during immune response in the non-human animal. Non-limiting examples of chimeric human/non-human MHC I polypeptides, genetically modified non-human animals expressing the same, and methods of making the same are described in U.S. Patent No. 9,591,835, U.S. Patent No. 9,615,550, U.S. Patent No. 10,045,516, U.S. Patent No. 10,779,520, U.S. Patent No. 10,869,466, International Publication No. WO 2013/063346, and International Publication No. WO 2014/164640, each of which is herein incorporated by reference in its entirety. HLA Class II [0069] In various embodiments, the invention provides a genetically modified rodent e.g., mouse, rat, etc.) that comprises in its genome a nucleotide sequence encoding a human or humanized MHC II complex, e.g., a human or humanized MHC II α and/or β polypeptide(s). The rodent may comprise in its genome a nucleotide sequence that encodes an MHC II complex that is partially human and partially non-human, e.g., a rodent that expresses a chimeric human/rodent MHC II complex (e.g., a rodent that expresses chimeric human/rodent MHC II α and β polypeptides). In one aspect, the rodent only expresses the human or humanized MHC II complex, e.g., a chimeric human/rodent MHC II complex, and does not express an endogenous non-human MHC II complex from an endogenous MHC II locus. In some embodiments, the rodent is incapable of expressing any endogenous rodent MHC II complex from an endogenous MHC II locus, but only expresses the human or humanized MHC II complex. In other embodiments, the rodent retains a nucleotide sequence encoding a functional endogenous mouse MHC II polypeptide. In various embodiments, the genetically modified rodent (e.g., mouse, rat, etc.) comprises in its germline a nucleotide sequence encoding a human or humanized MHC II complex, e.g., human or humanized MHC II α and/or β polypeptide(s). [0070] In one embodiment, provided herein is a rodent, e.g., a rat or a mouse, comprising in its genome, e.g., at an endogenous non-human MHC II locus, a nucleotide sequence encoding a human MHC II polypeptide. In another embodiment, provided herein is a rodent, e.g., a rat or a mouse, comprising in its genome, e.g., at an endogenous MHC II locus, a nucleotide sequence encoding a chimeric human/rodent MHC II polypeptide. Thus, also provided herein is a rodent that comprises in its genome, e.g., at an endogenous non-human MHC II locus, a nucleotide sequence(s) encoding a human or a chimeric human/non-human MHC II complex. [0071] The human portion of the MHC II α and β polypeptides described herein may be encoded by any of HLA-DP, -DQ, and –DR loci. A list of commonly used HLA antigens and alleles is described in Shankarkumar et al. ((2004) The Human Leukocyte Antigen (HLA) System, Int. J. Hum. Genet. 4(2):91-103), incorporated herein by reference. Shankarkumar et al. also present a brief explanation of HLA nomenclature used in the art. Additional information regarding HLA nomenclature and various HLA alleles can be found in Holdsworth et al. (2009) The HLA dictionary 2008: a summary of HLA-A, -B, -C, -DRB1/3/4/5, and DQB1 alleles and their association with serologically defined HLA-A, -B, -C, -DR, and –DQ antigens, Tissue Antigens 73:95-170, and a recent update by Marsh et al. (2010) Nomenclature for factors of the HLA system, 2010, Tissue Antigens 75:291-455, both incorporated herein by reference. Thus, the human or humanized MHC II polypeptide may be derived from any functional human HLA molecules described therein. [0072] In one specific aspect, the human portions of the humanized MHC II complex described herein are derived from human HLA-DR, e.g., HLA-DR4 or HLA-DR2. Typically, HLA-DR α chains are monomorphic, e.g., the α chain of HLA-DR complex is encoded by HLA-DRA gene (e.g., HLA-DRα1*01 gene). On the other hand, the HLA-DR β chain is polymorphic. Thus, HLA-DR4 comprises an α chain encoded by HLA-DRA gene and a β chain encoded by HLA- DRB1 gene (e.g., HLA-DRβ1*04 gene). As described herein below, HLA-DR4 is known to be associated with incidence of a number of autoimmune diseases, e.g., rheumatoid arthritis, type I diabetes, multiple sclerosis, etc. HLA-DR2 comprises an α chain encoded by HLA-DRA gene and a β chain encoded by HLA-DRB1 gene (e.g., HLA-DRβ1*02 gene). HLA-DR2 is known to be associated with a number of diseases, e.g., Goodpasture syndrome, multiple sclerosis, etc. In one embodiment of the invention, the HLA-DRA allele is HLA-DRα*01 allele, e.g., HLA- DRα*01:01:01:01. In another embodiment, the HLA-DRB allele is HLA-DRβ1*04, e.g., HLA- DRβ1*04:01:01. In another embodiment, the HLA-DRB allele is HLA- DRβ1*02, e.g., HLA- DRβ1*1501. [0073] In another specific embodiment, the human portions of the humanized MHC II complex described herein are derived from human HLA-DQ, e.g., HLA-DQ2 and HLA-DQ8. HLA-DQ2 comprises an α chain encoded by HLA-DQA gene (e.g., HLA-DQα1*05 gene). In one embodiment, HLA-DQα1*05 gene is HLA-DQα1*0501. HLA-DQ2 also comprises a β chain encoded by HLA-DQB gene (e.g., HLA-DQβ1*02 gene). HLA-DQ8 comprises an α chain encoded by HLA-DQA gene (e.g., HLA-DQα1*0301 gene). HLA-DQ8 also comprises a β chain encoded by HLA-DQB gene (e.g., HLA-DQβ1*0302 gene). HLA-DQ2.5 and HLA-DQ8 alleles are known to be associated with such diseases as Celiac disease and type I diabetes. [0074] In one aspect, a non-human portion of the chimeric human/non-human MHC II complex comprises transmembrane and/or cytoplasmic domains of an endogenous non-human (e.g., rodent, e.g., mouse, rat, etc.) MHC II complex. Thus, a non-human portion of the chimeric human/non-human MHC II α polypeptide may comprise transmembrane and/or cytoplasmic domains of an endogenous non-human MHC II α polypeptide. A non-human portion of the chimeric human/non-human MHC II β polypeptide may comprise transmembrane and/or cytoplasmic domains of an endogenous non-human MHC II β polypeptide. In one aspect, the rodent is a mouse, and non-human portions of the chimeric α and β polypeptides are derived from a mouse H-2E protein. Thus, non-human portions of the chimeric α and β polypeptides may comprise transmembrane and cytoplasmic domains derived from a mouse H-2E protein. In another aspect, the rodent is a mouse, and non-human portions of the chimeric α and β polypeptides are derived from a mouse H-2A protein. Thus, non-human portions of the chimeric α and β polypeptides may comprise transmembrane and cytoplasmic domains derived from a mouse H-2A protein. Although specific H-2E and H-2A sequences are contemplated in the Examples, any suitable sequences, e.g., polymorphic variants, conservative/non-conservative amino acid substitutions, etc., are encompassed herein. [0075] In various aspects of the invention, the sequence(s) encoding a chimeric human/non- human MHC II complex are located at an endogenous non-human MHC II locus (e.g., mouse H- 2A and/or H-2E locus). In one embodiment, this results in a replacement of an endogenous MHC II gene(s) or a portion thereof with a nucleotide sequence(s) encoding a human or humanized MHC II protein, e.g., a chimeric gene encoding a chimeric human/non-human MHC II protein described herein. Since the nucleotide sequences encoding MHC II α and β polypeptides are located in proximity to one another on the chromosome, a replacement can be designed to target the two genes either independently or together; both of these possibilities are encompassed herein. In one embodiment, the replacement comprises a replacement of an endogenous nucleotide sequence encoding an MHC II α and β polypeptides with a nucleotide sequence encoding a chimeric human/non-human MHC α polypeptide and a chimeric human/non-human MHC β polypeptide. In one aspect, the replacement comprises replacing nucleotide sequences representing one or more (e.g., two) endogenous MHC II genes. Thus, the rodent contains a chimeric human/non-human nucleotide sequence at an endogenous MHC II locus, and expresses a chimeric human/non-human MHC II protein from the endogenous non- human locus. [0076] Thus, provided herein is a rodent comprising at an endogenous MHC II gene locus a first nucleotide sequence encoding a chimeric human/non-human MHC II α polypeptide and a second nucleotide sequence encoding a chimeric human/non-human MHC II β polypeptide, wherein a human portion of the chimeric human/non-human MHC II α polypeptide comprises a human MHC II α extracellular domain and a human portion of the chimeric human/non-human MHC II β polypeptide comprises a human MHC II β extracellular domain, and wherein the chimeric human/non-human MHC II α and MHC II β polypeptides form a functional MHC II complex on a surface of a cell. [0077] A chimeric human/non-human polypeptide may be such that it comprises a human or a non-human leader (signal) sequence. In one embodiment, the chimeric MHC II α polypeptide comprises a non-human leader sequence of an endogenous MHC II α polypeptide. In one embodiment, the chimeric MHC II β polypeptide comprises a non-human leader sequence of an endogenous MHC II β polypeptide. In an alternative embodiment, the chimeric MHC II α and/or MHC II β polypeptide comprises a non-human leader sequence of MHC II α and/or MHC II β polypeptide, respectively, from another rodent, e.g., another rodent or another mouse strain. Thus, the nucleotide sequence encoding the chimeric MHC II α and/or MHC II β polypeptide may be operably linked to a nucleotide sequence encoding a non-human MHC II α and/or MHC II β leader sequence, respectively. In yet another embodiment, the chimeric MHC II α and/or MHC II β polypeptide comprises a human leader sequence of human MHC II α and/or human MHC II β polypeptide, respectively. In one embodiment, the human leader sequence of the human MHC II α is a leader sequence of human HLA-DRA and the human leader sequence of the human MHC II β polypeptide is a leader sequence of human HLA-DRβ1*04. In another embodiment, the human leader sequence of the human MHC II α is a leader sequence of human HLA-DRA and the human leader sequence of the human MHC II β polypeptide is a leader sequence of human HLA-DRβ1*02. In another embodiment, the human leader sequence of the human MHC II α is a leader sequence of human HLA-DQα1*05 and the human leader sequence of the human MHC II β polypeptide is a leader sequence of human HLA-DQβ1*02. In yet another embodiment, the human leader sequence of the human MHC II α is a leader sequence of human HLA-DQα1*0301 and the human leader sequence of the human MHC II β polypeptide is a leader sequence of human HLA-DQβ1*0302. [0078] A chimeric human/non-human MHC II α and/or MHC II β polypeptide may comprise in its human portion a complete or substantially complete extracellular domain of a human MHC II α and/or human MHC II β polypeptide, respectively. Thus, a human portion may comprise at least 80%, preferably at least 85%, more preferably at least 90%, e.g., 95% or more of the amino acids encoding an extracellular domain of a human MHC II α and/or human MHC II β polypeptide. In one example, substantially complete extracellular domain of the human MHC II α and/or human MHC II β polypeptide lacks a human leader sequence. In another example, the chimeric human/non-human MHC II α and/or the chimeric human/non-human MHC II β polypeptide comprises a human leader sequence. [0079] Moreover, the chimeric MHC II α and/or MHC II β polypeptide may be operably linked to (e.g., may be expressed under the control of) endogenous non-human promoter and regulatory elements, e.g., mouse MHC II α and/or MHC II β regulatory elements, respectively. Such arrangement may facilitate proper expression of the chimeric MHC II polypeptides in the rodent, e.g., during immune response in the rodent. [0080] Thus, in one embodiment, the invention relates to a genetically modified mouse that comprises in its genome a nucleotide sequence encoding a chimeric human/mouse MHC II complex, e.g., chimeric human/mouse MHC II α and β polypeptides. In one embodiment, a human portion of the chimeric human/mouse MHC II α polypeptide comprises a human MHC II α peptide binding or extracellular domain and a human portion of the chimeric human/mouse MHC II β polypeptide comprises a human MHC II β peptide binding or extracellular domain. In some embodiments, the mouse does not express a peptide binding or an extracellular domain of endogenous mouse α and/or β polypeptide from an endogenous mouse locus (e.g., H-2A and/or H-2E locus). In some embodiments, the mouse does not express functional peptide binding or extracellular domains of endogenous mouse MHC II polypeptides from endogenous mouse MHC II locus. In some embodiments, the mouse comprises a genome that lacks a gene that encodes a functional MHC class II molecule comprising an H-2Ab1, H-2Aa, H-2Eb1, H-2Eb2, H-2Ea, and a combination thereof. The peptide-binding domain of the human MHC II α polypeptide may comprise α1 domain and the peptide-binding domain of the human MHC II β polypeptide may comprise a β1 domain; thus, the peptide-binding domain of the chimeric MHC II complex may comprise human α1 and β1 domains. The extracellular domain of the human MHC II α polypeptide may comprise α1 and α2 domains and the extracellular domain of the human MHC II β polypeptide may comprise β1 and β2 domains; thus, the extracellular domain of the chimeric MHC II complex may comprise human α1, α2, β1 and β2 domains. In one embodiment, the mouse portion of the chimeric MHC II complex comprises transmembrane and cytosolic domains of mouse MHC II, e.g. mouse H-2E or H-2A (e.g., transmembrane and cytosolic domains of mouse H-2E α and β chains or mouse H-2A α and β chains). [0081] In one embodiment, a genetically modified mouse is provided, wherein the mouse comprises at an endogenous mouse MHC II locus a first nucleotide sequence encoding a chimeric human/mouse MHC II α polypeptide and a second nucleotide sequence encoding a chimeric human/mouse MHC II β polypeptide, wherein a human portion of the chimeric MHC II α polypeptide comprises an extracellular domain derived from an α polypeptide of a human HLA-DQ2 protein and a human portion of the chimeric MHC II β polypeptide comprises an extracellular domain derived from a β polypeptide of a human HLA-DQ2 protein, wherein a mouse portion of the chimeric MHC II α polypeptide comprises transmembrane and cytoplasmic domains of a mouse H-2A α chain and a mouse portion of the chimeric MHC II β polypeptide comprises transmembrane and cytoplasmic domains of a mouse H-2A β chain, and wherein the mouse expresses a functional chimeric HLA-DQ2/H-2A MHC II complex. In one embodiment the chimeric HLA-DQ2/H-2A MHC II complex comprises an MHC II α chain that includes extracellular domains (e.g., α1, and α2 domains) derived from HLA-DQ2 protein (HLA- DQα1*05 α1, and α2 domains) and transmembrane and cytoplasmic domains from a mouse H- 2A α chain, as well as an MHC II β chain that includes extracellular domains (e.g., β1 and β2 domains) derived from HLA-DQ2 (HLA-DQβ1*02 β1 and β2 domains) and transmembrane and cytoplasmic domains from mouse H-2A β chain. [0082] In one aspect, the mouse does not express functional endogenous H-2A and H-2E polypeptides from their endogenous mouse loci (e.g., the mouse does not express H-2Ab1, H- 2Aa, H-2Eb1, H-2Eb2, and H-2Ea polypeptides). In various embodiments, expression of the first and second nucleotide sequences is under the control of respective endogenous mouse promoters and regulatory elements (e.g., the first and second nucleotide sequences are operably linked to endogenous promoters and regulatory elements). In various embodiments of the invention, the first and the second nucleotide sequences are located on the same chromosome. In some aspects, the mouse comprises two copies of the chimeric MHC II locus containing the first and the second nucleotide sequences, while in other aspects, the mouse comprises one copy of the MHC II locus containing the first and the second nucleotide sequences. Thus, the mouse may be homozygous or heterozygous for the chimeric MHC II locus containing the first and the second nucleotide sequences. In various embodiments, the first and the second nucleotide sequences are comprised in the germline of the mouse. [0083] In various embodiments described herein, a mouse is provided that comprises a chimeric MHC II locus at an endogenous mouse MHC II locus, e.g., via replacement of endogenous mouse H-2A and H-2E genes. In one embodiment, the chimeric locus comprises a nucleotide sequence that encodes an extracellular domain of a human HLA-DQα1*05 and transmembrane and cytoplasmic domains of a mouse H-2Aα chain, as well as an extracellular domain of a human HLA-DQβ1*02 and transmembrane and cytoplasmic domains of a mouse H-2Aβ chain. The various domains of the chimeric locus are linked in such a fashion that the locus expresses a functional chimeric human/mouse MHC II complex. [0084] In various embodiments, a rodent, e.g., a mouse or rat) that expresses a functional chimeric MHC II protein from a chimeric MHC II locus as described herein displays the chimeric protein on a cell surface. In one embodiment, the rodent expresses the chimeric MHC II protein on a cell surface in a cellular distribution that is the same as observed in a human. In one aspect, the cell displays a peptide fragment (antigen fragment) bound to an extracellular portion (e.g., human HLA -DQ2 extracellular portion) of the chimeric MHC II protein. [0085] In various embodiments, a cell displaying the chimeric MHC II protein (e.g., HLA- DQ8/H-2A protein) is an antigen-presenting cell (APC) e.g., a macrophage, a dendritic cell, or a B cell. In some embodiments, the peptide fragment presented by the chimeric protein is derived from a tumor. In other embodiments, the peptide fragment presented by the chimeric MHC II protein is derived from a pathogen, e.g., a bacterium, a virus, or a parasite. Non-limiting examples of chimeric human/non-human MHC II polypeptides, genetically modified non-human animals expressing the same, and methods of making the same are described in U.S. Patent No. 8,847,005, U.S. Patent No. 9,043,996, U.S. Patent No. 9,585,373, U.S. Patent No. 9,700,025, U.S. Patent No. 10,219,493, U.S. Patent No. 10,986,822, U.S. Patent No. 11,219,195, International Publication No. WO 2013/063340, and International Publication No. WO 2014/164638, each of which is herein incorporated by reference in its entirety. [0086] The human or humanized MHC, e.g., classical HLA, molecule described herein may interact with other proteins on the surface of the same cell or a second cell. In some embodiments, the human or humanized MHC interacts with endogenous rodent proteins on the surface of said cell. The human or humanized MHC molecule may also interact with human or humanized proteins on the surface of the same cell or a second cell. In some embodiments, the second cell is a T cell, and the human or humanized MHC molecule interacts with T cell receptor (TCR) and/or its co-receptor CD4. In some embodiments, the T cell is a human T cell. In some embodiments, the TCR is a human or humanized TCR. [0087] In some embodiments, the genetically modified rodent exhibits one or more symptoms of a disease associated with the human or humanized MHC, e.g., classical HLA, molecule. In some embodiments, the genetically modified rodent exhibits one or more symptoms of a disease associated with the antigen presented by the human or humanized MHC. In some embodiments, the genetically modified rodent exhibits one or more symptoms of a disease associated with the combination of the human or humanized MHC, e.g., classical HLA, molecule and the antigen. [0088] In some embodiments, the genetically modified rodent comprises a nucleotide sequence, e.g., a nucleic acid, encoding at least an antigen presenting portion of an MHC, e.g., HLA, molecule that is associated with a disease as set forth in Table 1 below. In some embodiments, the antigen presented by the MHC, e.g., HLA, molecule comprises an antigen, or a portion thereof, that is associated with the disease as set forth in Table 1 below. In some embodiments, the genetically modified rodent exhibits one or more characteristics of the disease listed in Table 1 below. Table 1. Disease associated HLA molecules and alleles. HLA alleles nti n Multiple sclerosis DR2 or DR15 DRB1*15:01 Myelin- derived M lti l l r i DR13 DRB1*1303 d [0089] In various embodiments, the genetically modified rodent comprises a nucleotide sequence, e.g., a nucleic acid, encoding at least an antigen presenting portion of an HLA-DQ2.5 molecule. In one embodiment, the antigen is gliadin, or portion thereof. In one embodiment, the antigen presenting portion of an HLA-DQ2.5 molecule presents a peptide derived from gliadin. In various embodiments, the gliadin selected from the group consisting of: an α gliadin, a γ gliadin, and an ω gliadin. In various embodiments, the gliadin is an ω1, ω2, α1 or α2 gliadin. In one embodiment, the gliadin is an α1 gliadin. [0090] In various aspects, the genetically modified rodent exhibits one or more characteristics of celiac disease. In various embodiments, the genetically modified rodent comprises an activated effector T cell that specifically binds gliadin, or a portion thereof, presented in the context of the antigen presenting portion of HLA-DQ2.5. In various embodiments, the activated effector T cell expresses an activation-induced marker (AIM). In some embodiments, the AIM is selected from the group consisting of Ki67, IFNG, GZMB, 4-1BB, HLA-DR, ICOS, PD1, CD39, and CCL5. In some embodiments, the activated effector T cell is found in the blood, spleen and/or small intestine of the genetically modified rodent. Genetically Modified T cells [0091] In various aspects, the genetically modified rodent as described herein further comprises, in its periphery, a human T cell, e.g., a human T cell that has been genetically modified, e.g., an engineered human T cell. Human T cells as described herein may be prepared using various methods known in the art. In some embodiments, human T cells are enriched from healthy donor peripheral blood mononuclear cells (PBMCs). PBMCs may be isolated from a donor, e.g., human subject, via methods known in the art. For example, whole blood samples may be subject to density gradient centrifugation and the PBMC fraction isolated therefrom. Once PBMCs are isolated from whole blood, T cells can be further enriched via various methods known in the art. For example, T cells may be separated from non-T cells in a PBMC sample, e.g., B cells, monocytes, dendritic cells, using immunomagnetic negative selection. [0092] In some embodiments, the human T cells are maintained ex vivo in cell culture conditions that promote T cell survival and preserve T cell function prior to genetic modification and/or introduction into the genetically modified non-human animal as described herein. For example, the human T cells may be activated and/or expanded in vitro using various reagents and media known in the art. Human T cells that have been maintained ex vivo under suitable cell culture conditions and/or genetically modified as described herein, may be introduced into genetically modified non-human animals as described herein via any suitable method known in the art. For example, isolated human T cells, e.g., engineered human T cells, may be resuspended in a suitable excipient, and administered to a rodent as described herein, e.g., via intravenous injection. [0093] In various embodiments, the human T cell is genetically modified to express a recombinant nucleic acid that encodes (at least) a recombinant human TCR variable domain. As used herein, the term “TCR variable domain” encompasses a variable domain of a TCR α chain, e.g., TCR α variable domain, a variable domain of a TCR β chain, e.g., a TCR β variable domain, or a variable domain of a TCR comprising cognate TCR α and TCR β chains, e.g., both a TCR α variable domain and a TCR β variable domain. In some embodiments, the human T cell is genetically modified to express a recombinant nucleic acid that encodes (at least) a recombinant human TCR α variable domain. In some embodiments, the human T cell is genetically modified to express a recombinant nucleic acid that encodes (at least) a recombinant human TCR β variable domain. In some embodiments, the human T cell is genetically modified to express a recombinant nucleic acid that encodes (at least) a recombinant human TCR α variable domain and (at least) a recombinant human TCR β variable domain. In some embodiments, a human T cell as described herein expresses a recombinant nucleic acid that encodes a recombinant human TCR, i.e., variable and constant domains of the TCR α and β chains. In some embodiments, the human T cell expresses the recombinant human TCR variable domain and/or human TCR on its cell surface. In some embodiments, the recombinant human TCR variable domain and/or human TCR binds an antigen presented in the context of the antigen presenting portion of a human or humanized MHC as described herein. In some embodiments, the recombinant human TCR variable domains and/or TCR α and β chains are fused to a linker sequence. Non-limiting examples of linker sequences are a furin-cleavable linker and/or a self- cleavable 2A peptide (P2A, T2A, E2A, F2A). [0094] In some embodiments, the recombinant nucleic acid that encodes the recombinant human TCR variable domain is operably linked to a non-human promoter. In some embodiments, the non-human promoter controls expression of the recombinant human TCR variable domain. Non- limiting examples of non-human promoters include EF1α promoter, spleen focus-forming virus (SFFV) promoter, etc. In some embodiments, the recombinant nucleic acid that encodes the recombinant human TCR variable domain is operably linked to a non-human regulatory element. In some embodiments, the non-human regulatory element enhances expression of the recombinant human TCR variable domain. A non-limiting example of a non-human regulatory element that enhances expression of the recombinant human TCR variable is Woodchuck posttranscriptional regulatory element (WPRE). In some embodiments, the recombinant nucleic acid that encodes the recombinant human TCR variable domain is episomal. In some embodiments, the recombinant nucleic acid that encodes the recombinant human TCR variable domain replaces an endogenous TCR sequence at an endogenous TCR locus. In some embodiments, the recombinant nucleic acid that encodes the recombinant human TCR variable domain is randomly integrated into the genome. In some embodiments, the human T cell is an activated effector T cell. [0095] In some embodiments, the engineered T cell comprises a viral nucleic acid. In some embodiments, the viral nucleic acid encodes a 2A peptide. Non-limiting examples of 2A peptides include a T2A peptide, a P2A peptide, a F2A peptide, etc. In some embodiments, the T cell comprises an adeno-associated viral (AAV) nucleic acid. In one embodiment, the AAV nucleic acid is an AAV inverted terminal repeat (ITR). [0096] In some embodiments, the TCR of the engineered human T cell is an HLA-restricted, e.g., HLA-DQ2.5-restricted, TCR. In some embodiments, the TCR is an antigen-specific, e.g., gliadin-specific, e.g., α1 gliadin-specific, TCR. In some embodiments, the TCR is an HLA- restricted antigen-specific, e.g., HLA-DQ2.5-restricted ⍺1-gliadin-specific, TCR. [0097] In some embodiments, the recombinant human TCR variable domain comprises a TCR α variable domain encoded by a TRAV9-2 gene segment. In some embodiments, the TCR α variable domain comprises a complementary determining region (CDR) 3 that comprises an amino acid sequence of ALSDHYSSGSARQLT (SEQ ID NO: 10). In some embodiments, the TCR α variable domain is encoded by the TRAV9-2 gene segment and comprises a CDR3 that comprises an amino acid sequence of ALSDHYSSGSARQLT (SEQ ID NO: 10). In some embodiments, the recombinant human TCR variable domain comprises a TCR β variable domain encoded by a TRBV7-2 gene segment. In some embodiments, the TCR β variable domain comprises a CDR3 that comprises an amino acid sequence of ASSTAVLAGGPQY (SEQ ID NO: 14). In some embodiments, the TCR β variable domain is encoded by the TRBV7-2 gene segment and comprises a CDR3 that comprises an amino acid sequence of ASSTAVLAGGPQY (SEQ ID NO: 14). [0098] In some embodiments, the recombinant human TCR variable domain comprises a TCR α variable domain comprising a CDR1, CDR2 and CDR3 comprising the amino acid sequences set forth in SEQ ID NO: 8, SEQ ID NO: 9, and SEQ ID NO: 10, respectively. In some embodiments, the recombinant human TCR variable domain comprises a TCR β variable domain comprising a CDR1, CDR2 and CDR3 comprising the amino acid sequences set forth in SEQ ID NO: 12, SEQ ID NO: 13, and SEQ ID NO: 14, respectively. [0099] In some embodiments, the recombinant human TCR variable domain comprises a TCR α variable domain comprising the amino acid sequence as set forth in SEQ ID NO: 11. In some embodiments, the recombinant human TCR variable domain comprises a TCR β variable domain comprising the amino acid sequence as set forth in SEQ ID NO: 15. In one embodiment, the recombinant human TCR variable domain comprises a TCR α variable domain comprising the amino acid sequence as set forth in SEQ ID NO: 11 and a TCR β variable domain comprising the amino acid sequence as set forth in SEQ ID NO: 15. [00100] In some embodiments, the recombinant human TCR variable domain comprises a TCR α variable domain encoded by a TRAV26-1 gene segment. In some embodiments, the TCR α variable domain comprises a CDR3 that comprises an amino acid sequence of IVTNNNDMR (SEQ ID NO: 16). In some embodiments, the TCR α variable domain is encoded by the TRAV26-1 gene segment and comprises a CDR3 that comprises an amino acid sequence of IVTNNNDMR (SEQ ID NO: 16). In some embodiments, the recombinant human TCR variable domain comprises a TCR β variable domain encoded by a TRBV7-2 gene segment. In some embodiments, the TCR β variable domain comprises a CDR3 that comprises an amino acid sequence of ASSIRSTDTQY (SEQ ID NO: 17). In some embodiments, the TCR β variable domain is encoded by the TRBV7-2 gene segment and comprises a CDR3 that comprises an amino acid sequence of ASSIRSTDTQY (SEQ ID NO: 17). In embodiments, the recombinant TCR variable domain comprises a TCR α variable domain comprising a CDR3 comprising the amino acid sequence of IVTNNNDMR (SEQ ID NO: 16) and a TCR β variable domain comprising a CDR3 comprising the amino acid sequence of ASSIRSTDTQY (SEQ ID NO: 17). Genetically Modifying T Cells [00101] Various methods, systems, and compositions are provided herein to allow for introduction of a nucleic acid into a cell, e.g., genetically modifying human T cells. Such methods for introducing nucleic acids, genome editing agents, etc., include, for example, vector delivery, particle-mediated delivery, exosome-mediated delivery, lipid-nanoparticle (LNP)- mediated delivery, cell-penetrating-peptide-mediated delivery, etc. In one such example, electroporation is used. [00102] Introduction of nucleic acids, e.g., a recombinant nucleic acid that encodes the recombinant human TCR variable domain, genome editing agents, etc., may also be accomplished by virus-mediated delivery, such as AAV-mediated delivery or lentivirus-mediated delivery. Other exemplary viruses/viral vectors include retroviruses, adenoviruses, vaccinia viruses, poxviruses, and herpes simplex viruses. The viruses can integrate into the T cell genome or alternatively do not integrate into the T cell genome. The viruses can be replication-competent or can be replication-defective (e.g., defective in one or more genes necessary for additional rounds of virion replication and/or packaging). Viruses can cause transient expression, long- lasting expression (e.g., at least 1 week, 2 weeks, 1 month, 2 months, or 3 months), or permanent expression. In one example, the nucleic acid construct comprising a sequence encoding a recombinant human TCR variable domain(s) is introduced via lentivirus-mediated delivery. [00103] Such methods include introducing into the T cell one or more genome editing agents, thereby producing a genetically modified T cell, e.g., an engineered T cell. In some embodiments, the one or more genome editing agents comprises a nuclease agent or one or more nucleic acids encoding the nuclease agent. The nuclease agent (e.g., Cas9 protein) can cleave a nuclease target sequence (e.g., a guide RNA target sequence), thereby producing a modified T cell. For example, the nuclease agent can be a zinc finger nuclease (ZFN), a Transcription Activator-Like Effector Nuclease (TALEN), or a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-associated (Cas) protein and a guide RNA (gRNA) (e.g., a Cas9 protein and a guide RNA). In some embodiments, the nuclease agent target sequence includes an endogenous TCR α chain sequence and/or TCR β chain sequence, and the nuclease agent cleavage leads to the knockout of an endogenous TCR α chain gene and/or TCR β chain gene. In some embodiments, cleavage by the nuclease agent can result in disruption of an endogenous TCR α and/or endogenous TCR β gene so that a functional endogenous TCR α and/or endogenous TCR beta β is not produced. [00104] Methods of genetically modifying human T cells described herein also include introducing a nucleic acid construct comprising a sequence encoding a recombinant human TCR variable domain (or a nucleic acid construct comprising sequence(s) encoding recombinant human TCR α variable domain and/or a TCR β variable domain). In some embodiments, the nuclease agent and a nucleic acid construct comprising a sequence encoding a recombinant human TCR variable domain can be introduced into the cell or subject simultaneously or sequentially in any combination. For example, a nuclease agent (or nucleic acid encoding the nuclease agent or one or more nucleic acids encoding the nuclease agent) can be introduced into a cell or subject before introduction of a nucleic acid construct, simultaneously with a nucleic acid construct, or after introduction of a nucleic acid construct. In some embodiments, the nuclease agent (or nucleic acid encoding the nuclease agent or one or more nucleic acids encoding the nuclease agent) is introduced simultaneously with the nucleic acid construct (e.g., via electroporation). In some embodiments, the nuclease agent (or nucleic acid encoding the nuclease agent or one or more nucleic acids encoding the nuclease agent) is introduced before the nucleic acid construct (e.g., nuclease agent administered by electroporation, followed by infection with recombinant AAV/lentiviral nucleic acid construct). Likewise, a Cas protein (or nucleic acid encoding a Cas protein) and a guide RNA (or DNA encoding a guide RNA) can be introduced simultaneously or sequentially in any combination. For example, a Cas protein (or nucleic acid encoding a Cas protein) can be introduced into a cell or subject before introduction of a guide RNA (or DNA encoding the guide RNA), simultaneously with a guide RNA (or DNA encoding the guide RNA), or after introduction of a guide RNA (or DNA encoding the guide RNA). In addition, two or more of the components can be introduced into the cell or subject by the same delivery method or different delivery methods. Similarly, two or more of the components can be introduced into a subject by the same route of administration or different routes of administration. [00105] A guide RNA can be introduced into the cell in the form of an RNA molecule (e.g., in vitro transcribed RNA molecule) or in the form of a DNA molecule encoding the guide RNA. Likewise, protein components such as Cas proteins, ZFNs, or TALENs can be introduced into the cell in the form of DNA, RNA, or protein. In one example, a Cas protein and a guide RNA can be introduced together as a ribonucleoprotein (RNP) complex. In another example, a guide RNA and a Cas protein can both be introduced in the form of RNA (i.e., guide RNA and an mRNA molecule encoding the Cas protein). For example, the guide RNA and the mRNA molecule encoding the Cas protein can be delivered via LNP-mediated delivery. In another example, a guide RNA and a Cas protein can both be introduced in the form of DNA (e.g., in one or more lentiviral or AAV vectors encoding the guide RNA and Cas protein). Various methods for introducing a nuclease agent into a cell are known in the art. [00106] In some embodiments, the nuclease agent (e.g., Cas9 protein) can cleave a nuclease target sequence (e.g., a guide RNA target sequence) of endogenous TCR α and/or TCR β, and the nucleic acid construct comprising a sequence encoding a recombinant human TCR variable domain(s) can be inserted (e.g., via homology-directed repair). In some embodiments, the nucleic acid construct comprising a sequence encoding the recombinant human TCR variable domain (e.g., a human TCR α variable domain and/or a human TCR β variable domain) can be inserted at an endogenous TCR locus. In other embodiments, the nucleic acid construct comprising a sequence encoding the recombinant human TCR variable domain (e.g., a human TCR α variable domain and/or a human TCR β variable domain) is inserted at a locus that is not the endogenous TCR locus. In yet other embodiments, the nucleic acid construct comprising a sequence encoding the recombinant human TCR variable domain (e.g., a human TCR α variable domain and/or a human TCR β variable domain) is randomly integrated into the genome of a T cell. In yet other embodiments, the nucleic acid construct comprising a sequence encoding the recombinant human TCR variable domain (e.g., a human TCR α variable domain and/or a human TCR β variable domain) is episomal. [00107] In some embodiments, an antigen is introduced into a genetically modified non- human animal as described herein that has been engrafted with genetically modified human T cells, e.g., engineered human T cells, as described herein. In some embodiments, the genetically modified human T cell expresses a TCR comprising a TCR variable domain(s) that is specific for the antigen, such that upon introducing the antigen the genetically modified human T cell exhibits an effector memory phenotype. Non-limiting examples of an effector memory phenotype include CD45RO+, CD62L- T cells and CCR7lo, CD45RA- T cells. In some embodiments, the human T cell is found in the blood, spleen, or small intestine. In some embodiments, the human T cell expresses an AIM, e.g., Ki67, IFNG, GZMB, 4-1BB, HLA-DR, ICOS, PD1, CD39, CCL5, etc. [00108] Accordingly, described herein is a genetically modified rodent comprising: (a) in its genome, a first recombinant nucleic acid, wherein the first recombinant nucleic acid encodes (at least) an antigen presenting portion of a human or humanized MHC molecule, e.g., a classical HLA molecule, optionally wherein the antigen presenting portion of the human or humanized MHC molecule comprises α1, α2, and α3 domains of a classical HLA class I molecule; or α1, α2, β1, and β2 domains of a classical HLA class II molecule, and (b) in its periphery, a human T cell, wherein the human T cell is genetically modified to express a second recombinant nucleic acid that encodes a recombinant human T cell receptor (TCR) variable domain, wherein the human T cell expresses the recombinant human TCR variable domain on its cell surface, and wherein the recombinant human TCR variable domain binds an antigen presented in the context of the antigen presenting portion of the human or humanized MHC, e.g., classical HLA, molecule. Genetically Modified Rodents for Enhanced Engraftment of Human Cells [00109] In various aspects, a genetically modified rodent, e.g., a mouse or rat, that expresses at least an antigen presenting portion of a classical HLA and that comprises a genetically engineered human T cell, as described herein may further comprise one or more additional genetic modifications. The one or more genetic modifications may comprise modifications that enhance the development (e.g., the proper migration, homing, engraftment, survival, proliferation, production and/or differentiation) and/or proper function (e.g., phenotypic responses, such as immune responses) of transplanted human cells in the genetically modified rodent. In some embodiments, the genetically modified rodents as described herein further comprise genetic modifications that enhance the adoptive transfer of human T cells. [00110] The one or more genetic modifications that enhance the adoptive transfer of human cell, e.g., human T cells, may comprise knockout mutations that provide for an immunodeficient background and/or humanizations in which an exogenous nucleic acid sequence is inserted into the genome of the rodent to form a humanized gene that encodes a human or humanized polypeptide that promotes the development and/or function of transplanted human cells. In some instances, the human or humanized polypeptides may act on (e.g., bind) human biomolecules (e.g., receptors or ligands) for which the polypeptide’s endogenous rodent homolog is not cross-reactive, is insufficiently cross-reactive, and/or is expressed at non-optimal concentrations. A humanized gene may be designed to encode a human or humanized polypeptide which exhibits wildtype human function, such as reactivity with wildtype human biomolecules. For example, human or humanized receptor polypeptides may exhibit wildtype human receptor function (binding of human ligands and activation in response thereto) and human or humanized ligand polypeptides may exhibit wildtype human ligand function (binding and activation of human receptors). [00111] The exogenous nucleic acids forming these humanized genes may be randomly integrated into the rodent genome or may be inserted in a targeted manner into the endogenous locus of the homologous rodent gene that encodes the homologous rodent polypeptide, either at one or both alleles. The exogenous nucleic acid sequence may replace some or all of the genomic sequence at the endogenous locus, such as a homologous endogenous nucleic acid sequence (e.g., the coding region or a portion thereof). The humanized gene may effectively replace the endogenous gene such that the endogenous polypeptide normally encoded at the endogenous gene is effectively replaced by the human or humanized polypeptide. The sequence encoding a human or humanized polypeptide may be operably linked to a promoter, such as an endogenous promoter for the rodent’s homologous gene (e.g., operably linked to the native promoter at the endogenous locus for the homologous gene within the genome). By way of example, genetic modifications may be made to rodent (e.g., rodent) embryonic stem cells using VELOCIGENE® technology employing gap repair cloning. See, e.g., Valenzuela, et al. Nat Biotechnol. 2003 Jun;21(6):652-9, which is herein incorporated by reference in its entirety. Immunodeficient Background [00112] According to various aspects of the disclosure, it may be desirable to provide a rodent comprising an immune-compromised or immunodeficient background (e.g., lacking endogenous T-, B- and natural killer (NK) rodent cells), particularly where human cells are to be transplanted into the rodent. Accordingly, in some embodiments, the genetically modified rodents as described herein do not comprise, in their periphery, mature rodent B cells, mature rodent T cells, and/or rodent NK cells. Various strategies for developing immune-compromised or immune-deficient rodents, e.g., mice and rats, are well known in the art. For example, NOD Shi-SCID ycnull (NOG), NOD ltz-SCID yc-/- (NSG), and Balb/c Rag-/- yc-/- mice have all been well characterized. See, e.g., Drake, et al. Cell Mol Immunol. 2012 May;9(3):215-24, which is herein incorporated by reference in its entirety. Accordingly, a rodent described herein may lack a functioning endogenous immune system. [00113] In some embodiments, a rodent (e.g., mouse) provided herein may include at least one null allele for the Rag2 gene (“recombination activating gene 2”, wherein the coding sequence for the mouse gene may be found at Genbank Accession No. NM_009020.3, Gene symbol: Rag2). In some embodiments, a rodent (e.g., mouse) includes two null alleles for Rag2. In other words, the rodent (e.g., mouse) is homozygous null for Rag2. As another example, a rodent (e.g., mouse) includes at least one null allele for the Il2rg gene (“interleukin 2 receptor, gamma”, also known as the common gamma chain, or γC, wherein the coding sequence for the mouse gene may be found at Genbank Accession No. NM 013563.3, Gene symbol: Il2rg). In some embodiments, the rodent (e.g., mouse) includes two null alleles for Il2rg. In other words, the rodent (e.g., mouse) is homozygous null for Il2rg, i.e., it is Il2rg-/- (or Il2rgY/- where the Il2rg gene is located on the X chromosome as in mouse). In some embodiments, the rodent (e.g., mouse) includes a null allele for both Rag2 and Il2rg, i.e., it is Rag2-/- Il2rg-/- (or Rag2-/- Il2rgY/- where the Il2rg gene is located on the X chromosome as in mouse) (i.e. an “RG” background). In some embodiments, a rodent (e.g., mouse) provided herein may comprise at least one null allele for, e.g., a knockout mutation of, an (endogenous) recombination activating gene (Rag). In some embodiments, the (endogenous) Rag gene comprises an (endogenous) Rag2 gene, wherein the coding sequence for the mouse gene may be found, for example, at GenBank Accession No. NM_009020.4. In some instances, a rodent (e.g., mouse) provided herein comprises two null alleles for a Rag gene, e.g., is homozygous for the knockout mutation of the (endogenous) Rag, e.g., (endogenous) Rag2, gene. In other words, the rodent (e.g., mouse) is homozygous null for an (endogenous) Rag gene, e.g., (endogenous) Rag2 gene (Rag2null). As another example, a rodent (e.g., mouse) provided herein may comprise at least one null allele for an (endogenous) interleukin 2 receptor (Il2r) gene, e.g., an interleukin 2 receptor gamma gene (Il2rg or Il2rγ, also known as the common gamma chain, or γC), wherein the coding sequence for the mouse gene may be found at GenBank Accession No. NM_013563.4. In some instances, the rodent (e.g., mouse) provided herein comprises two null alleles for an Il2r gene, e.g., is homozygous for the knockout mutation of the (endogenous) Il2r, e.g., (endogenous) Il2rγ, gene. In other words, the rodent (e.g., mouse) is homozygous null for an (endogenous) Il2r gene, e.g., (endogenous) Il2rγ gene (Il2rγnull), i.e., it is Il2rγ-/- (or Il2rγY/- where the Il2rγ gene is located on the X chromosome as in mouse). In some instances, the rodent (e.g., mouse) provided herein comprises a null allele for both Rag2 and Il2rγ, i.e., it is Rag2-/- Il2rγ-/- (or Rag2-/- Il2rγY/- where the Il2rγ gene is located on the X chromosome as in mouse). A Rag2null Il2rγnull background may be abbreviated in certain models as “RG”. Interleukin 15 (IL-15) [00114] IL-15 (NCBI Gene IDs: 3600 (homo sapiens), Gene symbol: IL15; 16168 (mus musculus), Gene symbol: Il15) is a pleiotropic cytokine required for NK cell development and function and T cell homeostasis, being particularly important for the memory CD8+ T cell compartment. IL-15 is produced primarily by dendritic cells and macrophages and is trans- presented via IL-15/IL-15R complex to NK cells and T cells. It is a pro-inflammatory cytokine at the apex of a signaling cascade that induces production of other cytokines, recruits and activates T-cells and other inflammatory cells, promotes development and survival of NK cells, and promotes angiogenesis. IL-15 derived from endothelial cells stimulates trans-endothelial migration of T cells and recruitment to inflammatory cites. Expression of human or humanized IL-15 (hIL-15), particularly at physiological concentrations, may be particularly useful for maintaining xenografts, including lymphocyte tumors, and the development of NK cells in rodents. According to certain aspects of the disclosure, a rodent described herein may comprise an hIL-15 gene and/or otherwise express an hIL-15 polypeptide. The hIL-15 polypeptide may be a full-length human polypeptide (e.g., wildtype human polypeptide) or comprise a functional fragment thereof. According to certain aspects of the disclosure, the hIL-15 polypeptide may be a fully human IL-15 polypeptide. According to certain aspects of the disclosure, the mature hIL- 15 polypeptide (lacking a signal peptide and the removed proprotein sequence) may be fully human. According to certain aspects of the disclosure, the hIL15 gene may comprise an endogenous rodent Il155’ UTR. According to certain aspects of the disclosure, the hIL15 gene may comprise a human IL153’ UTR. According to certain aspects of the disclosure, the hIL15 gene may comprise an endogenous rodent Il155’ UTR, followed by an IL15 coding region that encodes an IL-15 polypeptide having a fully human mature polypeptide sequence, followed by a human IL153’ UTR. In some embodiments, the hIL15 gene is at an endogenous Il15 locus. In some embodiments, the hIL15 gene replaces an endogenous Il15 gene. In certain instances, the rodent (e.g., a mouse) comprises an hIL15 gene that comprises exons 3-6 of a human IL15 gene (e.g., replacing native exons 3-6 within the endogenous rodent Il15 locus of the genome of the genetically modified rodent). The hIL15 gene may comprise exons 1 and 2 of an endogenous rodent Il15 gene (e.g., the native exons within the endogenous rodent Il15 locus of the genome of the genetically modified rodent). The genetically modified rodent may be heterozygous or homozygous for the hIL15 gene. The genetically modified rodent may be modified in such a manner that it does not express any wild-type rodent IL-15 polypeptide. In some embodiments, the genetically modified rodent is homozygous for a replacement of the endogenous Il15 gene with the hIL15 gene, i.e., such that rodent does not comprise an endogenous Il15 gene or express a wild-type rodent IL-15 polypeptide. According to certain aspects of the disclosure, there is provided a genetically modified rodent embryonic stem cell comprising one or more copies of the hIL15 gene described herein or an embryo comprising such an embryonic stem cell (e.g., for making a genetically modified rodent comprising an hIL15 gene as described herein). By way of example, the hIL15 gene or the rodent, embryo, or embryonic stem cell comprising the hIL15 gene may be any of those described in U.S. Pat. No. 9,155,290 to Rojas, et al., issued on Oct. 13, 2015, which is herein incorporated by reference in its entirety, upon which additional modifications may be made in accordance with the disclosure herein. [00115] In some embodiments, provided are rodents that have been or are to be engrafted, e.g., administered (genetically modified) human T cells, in accordance with technologies described herein, wherein the rodent is genetically modified to further express a human IL-15 protein encoded by a nucleic acid operably linked to an Il15 promoter. As used herein, “human IL-15 protein”, means a protein that is a wild-type (or native) human IL-15 protein or a variant of a wild-type (or native) human IL-15 protein, which retains one or more signaling functions of a wild-type (or native) human IL-15 protein, e.g., which allows for stimulation of (or signaling via) the human IL-15 receptor, and/or which is capable of binding to the human IL-15 receptor alpha subunit of the human IL-15 receptor, and/or which is capable of binding to IL-2R beta/IL-15R beta and the common γ-chain (γc). Also encompassed by the term “human IL-15 protein” are fragments of a wild-type human IL-15 protein (or variants thereof), which retain one or more signaling functions of a wild-type human IL-15 protein, e.g., a fragment of a human IL-15 protein, which allows for stimulation of (or signaling via) the human IL-15 receptor, and/or which is capable of binding to the human IL-15 receptor alpha subunit of the human IL-15 receptor, and/or which is capable of binding to IL-2R beta/IL-15R beta and the common γ-chain (γc). [00116] The term “human IL-15 protein” also encompasses fusion proteins, i.e., chimeric proteins, which include one or more fragments of a wild-type human IL-15 protein (or a variant thereof) and which retain one or more signaling functions of a wild-type human IL-15 protein, e.g., as described above. A fusion protein which includes one or more fragments of a wild-type human IL-15 protein (or a variant thereof) may also be referred to herein as a humanized IL-15 protein. [00117] A nucleic acid sequence that encodes a human IL-15 protein is, therefore, a polynucleotide that includes a coding sequence for a human IL-15 protein, i.e., a wild-type human IL-15 protein, a variant of a wild-type human IL-15 protein, a fragment of a wild-type human IL-15 protein (or a variant thereof) which retains one or more signaling functions of a wild-type human IL-15 protein, or fusion proteins, i.e., chimeric proteins, which include one or more fragments of a wild-type human IL- 15 protein (or a variant thereof) and which retain one or more signaling functions of a wild-type human IL-15 protein, e.g., as described above. [00118] IL-15 (also known as “Interleukin 15”) is a cytokine that stimulates the proliferation of T lymphocytes. Polypeptide sequence for wild-type human IL-15 and the nucleic acid sequence that encodes wild-type human IL-15 may be found at Genbank Accession Nos. NP_000576.1 and NM_000585.5 (isoform 1 and transcript variant 3), NP 751915.1 and NM_172175.3 (isoform 2 and transcript variant 2). The genomic locus encoding the wild-type human IL-15 protein may be found in the human genome at Chromosome 4; NC 000004.12 (141636583-141733987) or NG_029605.2 (4988-102392). In some embodiments, the human IL15 locus (e.g., NM_000585.5) includes 8 exons, with exons 3-8 being coding exons. As such, in some embodiments, a nucleic acid sequence including coding sequence for human IL15 includes one or more of exons 3-8 of the human IL15 gene. In some instances, the nucleic acid sequence also includes aspects of the genomic locus of the human IL15, e.g., introns, 3' and/or 5' untranslated sequence (UTRs). In some instances, the nucleic acid sequence includes whole regions of the human IL15 genomic locus. In some instances, the nucleic acid sequence includes exons 5-8 of the human IL15 genomic locus (i.e., coding exons 3-6). [00119] In the humanized IL-15 rodents described herein, the nucleic acid sequence that encodes a human IL-15 protein is operably linked to one or more regulatory sequences of an Il15 gene, e.g., a regulatory sequence of an Il15 gene of the rodent. Rodent, e.g., mouse, Il15 regulatory sequences are those sequences of the rodent Il15 genomic locus that regulate the rodent IL-15 expression, for example, 5' regulatory sequences, e.g., the Il15 promoter, Il155' untranslated region (UTR), etc.; 3' regulatory sequences, e.g., the 3 'UTR; and enhancers, etc. Mouse Il15 is located on Chromosome 8, NC_000074.7 (c83129883-83058253), and the mouse Il15 coding sequence may be found at Genbank Accession Nos. NM_008357.3 (transcript variant 1); NM_001254747.2 (transcript variant 2). The regulatory sequences of mouse Il15 are well defined in the art, and may be readily identified using in silico methods, e.g., by referring to the above Genbank Accession Nos. on the UCSC Genome Browser, on the world wide web at genome.ucsc.edu, or by experimental methods as described in the art. In some instances, e.g., when the nucleic acid sequence that encodes a human IL-15 protein is located at the mouse Il15 genomic locus, the regulatory sequences operably linked to the human IL15 coding sequence are endogenous, or native, to the mouse genome, i.e., they were present in the mouse genome prior to integration of human nucleic acid sequences. [00120] In some instances, the humanized IL-15 rodent, e.g., mouse, is generated by the random integration, or insertion, of a human nucleic acid sequence encoding a human IL-15 protein (including fragments as described above), i.e., a “human IL-15 nucleic acid sequence”, or “human IL-15 sequence”, into the genome of the rodent. Typically, in such embodiments, the location of the nucleic acid sequence encoding a human IL-15 protein in the genome is unknown. In other instances, the humanized IL-15 rodent is generated by the targeted integration, or insertion, of human IL-15 nucleic acid sequence into the genome of the rodent, by, for example, homologous recombination. In homologous recombination, a polynucleotide is inserted into the host genome at a target locus while simultaneously removing host genomic material, e.g., 50 base pairs (bp) or more, 100 bp or more, 200 bp or more, 500 bp or more, 1 kB or more, 2 kB or more, 5 kB or more, 10 kB or more, 15 kB or more, 20 kB or more, or 50 kB or more of genomic material, from the target locus. So, for example, in a humanized IL-15 mouse including a nucleic acid sequence that encodes a human IL-15 protein created by targeting human IL15 nucleic acid sequence to the mouse Il15 locus, human IL15 nucleic acid sequence may replace some or all of the mouse sequence, e.g., exons and/or introns, at the Il15 locus. In some such instances, a human IL15 nucleic acid sequence is integrated into the mouse Il15 locus such that expression of the human IL15 sequence is regulated by the native, or endogenous, regulatory sequences at the mouse Il15 locus. In other words, the regulatory sequence(s) to which the nucleic acid sequence encoding a human IL-15 protein is operably linked are the native Il15 regulatory sequences at the mouse Il15 locus. [00121] In some instances, the integration of a human IL15 sequence does not affect the transcription of the gene into which the human IL15 sequence has integrated. For example, if the human IL15 sequence integrates into a coding sequence as an intein, or the human IL15 sequence includes a 2A peptide, the human IL15 sequence will be transcribed and translated simultaneously with the gene into which the human IL15 sequence has integrated. In other instances, the integration of the human IL15 sequence interrupts the transcription of the gene into which the human IL15 sequence has integrated. For example, upon integration of the human IL15 sequence by homologous recombination, some or all of the coding sequence at the integration locus may be removed, such that the human IL15 sequence is transcribed instead. In some such instances, the integration of a human IL15 sequence creates a null mutation, and hence, a null allele. A null allele is a mutant copy of a gene that completely lacks that gene's normal function. This can be the result of the complete absence of the gene product (protein, RNA) at the molecular level, or the expression of a non-functional gene product. At the phenotypic level, a null allele is indistinguishable from a deletion of the entire locus. [00122] In some instances, the humanized IL-15 rodent, e.g., mouse, includes one copy of the nucleic acid sequence encoding a human IL-15 protein. For example, the rodent may be heterozygous for the nucleic acid sequence. In other words, one allele at a locus will include the nucleic acid sequence, while the other will be the endogenous allele. For example, as discussed above, in some instances, a human IL15 nucleic acid sequence is integrated into the rodent, e.g., mouse, Il15 locus such that it creates a null allele for the rodent Il15. In some such embodiments, the humanized IL-15 rodent may be heterozygous for the nucleic acid sequence encoding human IL-15, i.e., the humanized IL-15 rodent includes one null allele for the rodent Il15 (the allele including the nucleic acid sequence) and one endogenous Il15 allele (wild-type or otherwise). In other instances, the humanized IL-15 rodent includes two copies of the nucleic acid sequence encoding a human IL-15 protein. For example, the rodent, e.g., mouse, may be homozygous for the nucleic acid sequence, i.e., both alleles for a locus in the diploid genome will include the nucleic acid sequence, i.e., the humanized IL-15 rodent includes two null alleles for the rodent Il15 (the allele including the nucleic acid sequence). [00123] Human IL-15 polypeptides, loci encoding human IL-15 polypeptides and rodents expressing human IL-15 polypeptides are described in WO 2016/168212, which is herein incorporated by reference in its entirety. SIRPα [00124] Signal regulatory protein α (SIRPα or SIRPa; NCBI Gene IDs: 140885 (homo sapiens), Gene symbol: SIRPA; 19261 (mus musculus), Gene symbol: Sirpa) is expressed on immune cells of the myeloid lineage and functions as an inhibitory receptor. CD47 is a transmembrane protein that binds to SIRPα on macrophages to negatively regulate phagocytosis. Expression of human or humanized SIRPα (hSIRPα) on the macrophages of a rodent host can lead to decreased phagocytosis of transplanted human CD47-expressing cells and may be particularly useful for achieving improved human cell engraftment in rodents. According to certain aspects of the disclosure, a rodent described herein may comprise an hSIRPA gene and/or otherwise express an hSIRPα polypeptide. The hSIRPα polypeptide may be a full-length human polypeptide (e.g., wildtype human polypeptide) or comprise a functional fragment thereof. According to certain aspects of the disclosure, the hSIRPα polypeptide may be a fully human SIRPα polypeptide. According to certain aspects of the disclosure, the hSIRPα polypeptide comprises a human extracellular domain (e.g., the extracellular portion of a human SIRPα protein). For example, the hSIRPα polypeptide may comprise residues 28-362 of the amino acid sequence set forth in NCBI Ref Seq: NP_001035111.1, which is herein incorporated by reference in its entirety, or comprise an amino acid sequence that is substantially identical (e.g., at least 90, 95, 96, 97, 98, or 99% identical) to residues 28-362. According to certain aspects of the disclosure, a rodent may express a humanized (chimeric) SIRPα polypeptide. For example, the humanized SIRPα polypeptide may comprise a human extracellular domain and an endogenous rodent (e.g., mouse) intracellular domain (e.g., the intracellular portion of a rodent SIRPα protein). The chimeric polypeptide may be a rodent SIRPα polypeptide having its extracellular domain, or a substantial portion thereof, replaced with a human SIRPα extracellular domain. In some embodiments, the hSIRPA gene is at an endogenous sirpa locus. In some embodiments, the hSIRPA gene replaces an endogenous sirpa gene. In certain instances, the rodent (e.g., a mouse) may have an hSIRPA gene that comprises exons 2, 3, and 4 of a human SIRPA gene (e.g., replacing native exons 2, 3, and 4 within the endogenous rodent sirpa locus of the genome of the genetically modified rodent). The hSIRPA gene may comprise exons 1, 5, 6, 7, and 8 of an endogenous rodent sirpa gene (e.g., the native exons within the endogenous rodent sirpa locus of the genome of the genetically modified rodent). The genetically modified rodent may be heterozygous or homozygous for the hSIRPA gene. The genetically modified rodent may be modified in such a manner that it does not express any wild-type rodent SIRPα polypeptide. In some embodiments, the genetically modified rodent is homozygous for a replacement of the endogenous sirpa gene with the hSIRPA, i.e., such that the rodent does not comprise an endogenous sirpa gene or express a wild-type rodent SIRPα polypeptide. According to certain aspects of the disclosure, there is provided a genetically modified rodent embryonic stem cell comprising one or more copies of the hSIRPA gene described herein or an embryo comprising such an embryonic stem cell (e.g., for making a genetically modified rodent comprising an hSIRPA gene as described herein). By way of example, the hSIRPA gene or the rodent, embryo, or embryonic stem cell comprising the hSIRPA gene may be any of those described in U.S. Pat. No. 9,193,977 to Murphy, et al., issued on Nov. 24, 2015, which is herein incorporated by reference in its entirety, upon which additional modifications may be made in accordance with the disclosure herein. In some instances, the hSIRPA gene may be a randomly integrated transgene (“SIRPAtg”). By way of example, the hSIRPA gene or the rodent, embryo, or embryonic stem cell comprising the hSIRPA gene may be any of those described in US Pat. No. 9,402,377 to Flavell et al., issued on Aug. 2, 2016; or Strowig, et al., Proc Natl Acad Sci U S A. 2011 Aug 9;108(32):13218-23, each of which is herein incorporated by reference in its entirety, upon which additional modifications may be made in accordance with the disclosure herein. [00125] In some embodiments, rodents are provided that have been or are to be engrafted with human cells according to methods described herein, wherein the genetically modified rodents provided herein further express a human or humanized SIRPα protein encoded by a nucleic acid operably linked to a sirpa promoter. [00126] Signal regulatory proteins (SIRPs) constitute a family of cell surface glycoproteins which are expressed on lymphocytes, myeloid cells (including macrophages, neutrophils, granulocytes, myeloid dendritic cells, and mast cells) and neurons (e.g., see Barclay and Brown, 2006, Nat Rev Immunol 6, 457-464). The reported SIRP genes encode at least SIRPα, SIRP3, SIRPβ, SIRPγ, and SIRP8 and can be categorized by their respective ligands and types of signaling in which they are involved. SIRPα (also referred to as CD172A, SHPS1, P84, MYD-1, BIT and PTPNS1) is expressed on immune cells of the myeloid lineage and functions as an inhibitory receptor via an immunoreceptor tyrosine-based inhibitory motif (ITIM). SIRPα expression has also been observed on neurons. Reported ligands for SIRPα include, most notably, CD47, but also include surfactant proteins A and D. The role of SIRPα, in particular, has been investigated in respect of its inhibitory role in the phagocytosis of host cells by macrophages. For example, CD47 binding to SIRPα on macrophages, triggers inhibitory signals that negatively regulates phagocytosis. Alternatively, positive signaling effects mediated through SIRPα binding have been reported (Shultz et al., 1995, J Immunol 154, 180-91). SIRPα has been shown to improve cell engraftment in immunodeficient mice (Strowig et al. Proc Natl Acad Sci USA 2011; 108: 13218-13223). [00127] Polypeptide sequences for wild-type human SIRPα and the nucleic acid sequences that encode wild-type human SIRPα may be found at Genbank Accession Nos. NP_001035111.1 and NM_001040022.1 (isoform 1 and transcript variant 1); NP_001035112.1 and NM_001040023.2 (isoform 1 and transcript variant 2); NP_001317657.1 and NM_001330728.1 (isoform 2 and transcript variant 4); and NP_542970.1 and NM_080792.3 (isoform 1 and transcript variant 3). The SIRPα gene is conserved in at least chimpanzee, Rhesus monkey, dog, cow, mouse, rat, and chicken. The genomic locus encoding the wild-type human SIRPα protein may be found in the human genome at Chromosome 20; NC_000020.11 (1894167-1940592). In some embodiments, human SIRPα protein is encoded by exons 2 through 9 at this locus. As such, in some embodiments, a nucleic acid sequence including coding sequence for human SIRPα includes one or more of exons 2-9 of the human SIRPA gene. In some instances, the nucleic acid sequence also includes aspects of the genomic locus of the human SIRPA, e.g., introns, 3' and/or 5' untranslated sequence (UTRs). In some instances, the nucleic acid sequence includes whole regions of the human SIRPA genomic locus. In some instances, the nucleic acid sequence includes exons 2-4 of the human SIRPA genomic locus. [00128] Representative mouse SIRPα cDNA, mouse SIRPα protein, human SIRPα cDNA, and human SIRPα protein sequences are described in U.S. Pat. No. 11,019,810, which is herein incorporated by reference in its entirety. A representative humanized SIRPα protein is set forth in SEQ ID NO: 18. [00129] In some embodiments, the rodents provided herein express humanized SIRPα proteins on the surface of immune cells (e.g., myeloid cells) of the rodents resulting from a genetic modification of an endogenous locus of the rodent that encodes a SIRPα protein. Suitable examples described herein include rodents, in particular, mice. [00130] A humanized SIRPA gene, in some embodiments, comprises genetic material from a heterologous species (e.g., humans), wherein the humanized SIRPA gene encodes a SIRPα protein that comprises the encoded portion of the genetic material from the heterologous species. In some embodiments, a humanized SIRPA gene of the present disclosure comprises genomic DNA of a heterologous species that corresponds to the extracellular portion of a SIRPα protein that is expressed on the plasma membrane of a cell. Rodents, embryos, cells and targeting constructs for making rodents, non-human embryos, and cells containing said humanized SIRPα gene are also provided. [00131] In some embodiments, an endogenous sirpa gene is deleted. In some embodiments, an endogenous sirpa gene is altered, wherein a portion of the endogenous sirpa gene is replaced with a heterologous sequence (e.g., a human SIRPA sequence in whole or in part). In some embodiments, all or substantially all of an endogenous sirpa gene is replaced with a heterologous gene (e.g., a human SIRPA gene). In some embodiments, a portion of a heterologous SIRPA gene is inserted into an endogenous non-human sirpa gene at an endogenous sirpa locus. In some embodiments, the heterologous gene is a human gene. In some embodiments, the modification or humanization is made to one of the two copies of the endogenous sirpa gene, giving rise to a rodent which is heterozygous with respect to the humanized SIRPA gene. In other embodiments, a rodent is provided that is homozygous for a humanized SIRPA gene. [00132] A rodent of the present disclosure contains a human SIRPA gene in whole or in part at an endogenous non-human sirpa locus. Thus, such rodents can be described as having a heterologous SIRP gene. The replaced, inserted or modified SIRPA gene at the endogenous sirpa locus can be detected using a variety of methods including, for example, PCR, Western blot, Southern blot, restriction fragment length polymorphism (RFLP), or a gain or loss of allele assay. In some embodiments, the rodent is heterozygous with respect to the humanized SIRPA gene. [00133] In various embodiments, a humanized SIRPA gene according to the present disclosure includes a SIRPA gene that has a second, third and fourth exon each having a sequence at least 50% (e.g., 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identical to a second, third and fourth exon that appear in a human SIRPA gene. [00134] In various embodiments, a humanized SIRPA gene according to the present disclosure includes a SIRPA gene that has a nucleotide coding sequence (e.g., a cDNA sequence) at least 50% (e.g., 50%, 55%, 60%0, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identical to nucleotides 352-1114 that appear in a human SIRPA cDNA sequence. [00135] In various embodiments, a humanized SIRPα protein produced by a rodent of the present disclosure has an extracellular portion having a sequence that is at least 50% (e.g., 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identical to an extracellular portion of a human SIRPα protein. [00136] In various embodiments, a humanized SIRPα a protein produced by a rodent of the present disclosure has an extracellular portion having a sequence that is at least 50% (e.g., 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) identical to amino acid residues 28-362 that appear in a human SIRPα protein. [00137] Compositions and methods for making rodents that express a humanized SIRPα protein, including specific polymorphic forms or allelic variants (e.g., single amino acid differences), are provided, including compositions and methods for making rodents that express such proteins from a human promoter and a human regulatory sequence. In some embodiments, compositions and methods for making rodents that express such proteins from an endogenous promoter and an endogenous regulatory sequence are also provided. The methods include inserting the genetic material encoding a human SIRPα protein in whole or in part at a precise location in the genome of a rodent that corresponds to an endogenous sirpa gene thereby creating a humanized SIRPA gene that expresses a SIRPα protein that is human in whole or in part. In some embodiments, the methods include inserting genomic DNA corresponding to exons 2-4 of a human SIRPA gene into an endogenous sirpa gene of the rodent thereby creating a humanized gene that encodes a SIRPα protein that contains a human portion containing amino acids encoded by the inserted exons. [00138] A humanized SIRPA gene approach employs a relatively minimal modification of the endogenous gene and results in natural SIRPα-mediated signal transduction in the rodent, in various embodiments, because the genomic sequence of the SIRPα sequences are modified in a single fragment and therefore retain normal functionality by including necessary regulatory sequences. Thus, in such embodiments, the SIRPA gene modification does not affect other surrounding genes or other endogenous sirpa genes. Further, in various embodiments, the modification does not affect the assembly of a functional receptor on the plasma and maintains normal effector functions via binding and subsequent signal transduction through the cytoplasmic portion of the receptor which is unaffected by the modification. [00139] In addition to mice having humanized SIRPA genes as described herein, also provided herein are other genetically modified rodents that comprise humanized SIRPA genes. In some embodiments, such rodents comprise a humanized SIRPA gene operably linked to an endogenous sirpa promoter. In some embodiments, such rodents express a humanized SIRPA protein from an endogenous locus, wherein the humanized SIRPA protein comprises amino acid residues 28-362 of a human SIRPα protein. [00140] Humanized SIRPα polypeptides, loci encoding humanized SIRPα polypeptides and rodents expressing humanized SIRPα polypeptides are described in U.S. Pat. No. 11,019,810, WO 2014/039782, WO 2014/071397, and WO 2016/168212, each of which is herein incorporated by reference in its entirety. CD47 [00141] CD47 (NCBI Gene IDs: 961 (homo sapiens), Gene symbol: CD47; 16423 (mus musculus), Gene symbol: Cd47) is involved in bidirectional signaling that regulates a variety of cell-to-cell responses such as, for example, inhibition of phagocytosis and T cell activation. CD47 interacts with several membrane integrins, most commonly integrin αVβ3, resulting in complexes that affect a range of cell functions including adhesion, spreading and migration. Binding of the secreted ligand thrombospondin-1 (TSP-1) to CD47 influences several fundamental cellular functions including cell migration and adhesion, cell proliferation or apoptosis, and plays a role in the regulation of angiogenesis and inflammation. With respect to phagocytosis, CD47 acts as a “don't eat me” signal by binding to SIRPα on macrophages of the immune system and has been found to be upregulated in certain hematologic cancers and indicated in evasion of tumor surveillance, making it a therapeutic target for cancer. With respect to genetically modified rodents expressing hSIRPα, and especially those which do not express endogenous wildtype SIRPα, expression of human or humanized CD47 (hCD47) may be particularly useful for preserving proper CD47/SIRPα signaling within the animal. According to certain aspects of the disclosure, a rodent described herein may comprise an hCD47 gene and/or otherwise express an hCD47 polypeptide. The hCD47 polypeptide may be a full-length human polypeptide (e.g., wildtype human polypeptide) or comprise a functional fragment thereof. According to certain aspects of the disclosure, the hCD47 polypeptide may be a fully human CD47 polypeptide. According to certain aspects of the disclosure, the hCD47 polypeptide comprises a human extracellular domain (e.g., the extracellular portion of a human CD47 protein). For example, the hCD47 polypeptide may comprise residues 16-292, 19-127, 19-141, or 19-292 of the amino acid sequence set forth in NCBI Ref Seq: XP_005247966.1, NP_942088.1, XP_005247965.1, or NP_001768.l, each of which is herein incorporated by reference in its entirety, or comprise an amino acid sequence that is substantially identical (e.g., at least 90, 95, 96, 97, 98, or 99% identical) to residues 16-292, 19-127, 19-141, or 19-292. According to certain aspects of the disclosure, a rodent may express a humanized (chimeric) CD47 polypeptide. For example, the humanized CD47 polypeptide may comprise a human extracellular domain and an endogenous rodent (e.g., mouse) intracellular domain (e.g., the intracellular portion of a rodent CD47 protein). The chimeric polypeptide may be a rodent CD47 polypeptide having its extracellular domain, or a substantial portion thereof, replaced with a human CD47 extracellular domain. In certain instances, the rodent may be a rodent (e.g., a mouse) having an hCD47 gene that comprises exons 2-7 of a human CD47 gene (e.g., replacing native exons 2-7 within the endogenous rodent Cd47 locus of the genome of the genetically modified rodent). The hCD47 gene may comprise exon 1 and any exons downstream of exon 7 of an endogenous rodent Cd47 gene (e.g., the native exons within the endogenous rodent Cd47 locus of the genome of the genetically modified rodent). The genetically modified animal may be heterozygous or homozygous for the hCD47 gene. The genetically modified rodent may be modified in such a manner that it does not express any wild-type rodent CD47 polypeptide. According to certain aspects of the disclosure, there is provided a genetically modified rodent embryonic stem cell comprising one or more copies of the hCD47 gene described herein or an embryo comprising such an embryonic stem cell (e.g., for making a genetically modified rodent comprising an hCD47 gene as described herein). By way of example, the hCD47 gene or the rodent, embryo, or embryonic stem cell comprising the hCD47 gene may be any of those described in U.S. Pat. No. 9,730,435 to McWhirter, et al., issued on Aug. 15, 2017, which is herein incorporated by reference in its entirety, upon which additional modifications may be made in accordance with the disclosure herein. IL-3 [00142] IL-3 (NCBI Gene IDs: 3562 (homo sapiens), Gene symbol: IL3; 16187 (mus musculus), Gene symbol: Il3) is a cytokine produced by activated T cells, monocytes, macrophages and stroma cells and promotes the proliferation and differentiation of a broad range of myeloid progenitor cells, including those that give rise to granulocytes, monocytes, and dendritic cells, in conjunction with other cytokines (e.g., EPO, GM-CSF and IL-6). Expression of human or humanized IL-3 (hIL-3) may be particularly useful for promoting the proper development and/or function of human myeloid cells within a rodent. According to certain aspects of the disclosure, a rodent described herein may comprise an hIL3 gene and/or otherwise express an hIL-3 polypeptide. The hIL-3 polypeptide may be a full-length human polypeptide (e.g., wildtype human polypeptide) or comprise a functional fragment thereof. According to certain aspects of the disclosure, the hIL-3 polypeptide may be a fully human IL-3 polypeptide. According to certain aspects of the disclosure, the hIL3 gene may comprise a human IL35’ UTR. According to certain aspects of the disclosure, the hIL3 gene may comprise a human IL33’ UTR. According to certain aspects of the disclosure, the hIL3 gene may comprise a human IL35’ UTR, followed by a human IL3 coding region, followed by a human IL33’ UTR. For example, the rodent may comprise a replacement of a nucleic acid comprising the rodent’s endogenous Il35’ UTR, endogenous Il3 coding region, and endogenous Il33’ UTR with a nucleic acid comprising a human I-35’ UTR, human IL3 coding region, and human IL33’ UTR. The genetically modified animal may be heterozygous or homozygous for the hIL3 gene. The genetically modified rodent may be modified in such a manner that it does not express any wild-type rodent IL-3 polypeptide. According to certain aspects of the disclosure, there is provided a genetically modified rodent embryonic stem cell comprising one or more copies of the hIL3 gene described herein or an embryo comprising such an embryonic stem cell (e.g., for making a genetically modified rodent comprising an hIL3 gene as described herein). By way of example, the hIL3 gene or the rodent, embryo, or embryonic stem cell comprising the hIL3 gene may be any of those described in U.S. Pat. No. 8,541,646 to Stevens, et al., issued on Sep. 24, 2013, which is herein incorporated by reference in its entirety, upon which additional modifications may be made in accordance with the disclosure herein. GM-CSF [00143] Granulocyte-macrophage colony-stimulating factor (GM-CSF; Gene IDs: 1437 (homo sapiens), Gene symbol: CSF2; 12981 (mus musculus), Gene symbol: Csf2) is a cytokine secreted by macrophages, T cells, mast cells and natural killer cells in response to proinflammatory stimuli and stimulates hematopoietic stem and progenitor cells to produce granulocytes (neutrophils, eosinophils, and basophils) and monocytes. Expression of human or humanized GM-CSF (hGM-CSF) may be particularly useful for promoting the proper development and/or function of human granulocytes, monocytes, and macrophages within a rodent. According to certain aspects of the disclosure, a rodent described herein may comprise an hCSF2 gene and/or otherwise express an hGM-CSF polypeptide. The hGM-CSF polypeptide may be a full-length human polypeptide (e.g., wildtype human polypeptide) or comprise a functional fragment thereof. According to certain aspects of the disclosure, the hCSF2 polypeptide may be a fully human GM-CSF polypeptide. According to certain aspects of the disclosure, the hCSF2 gene may comprise a human CSF25’ UTR. According to certain aspects of the disclosure, the hCSF2 gene may comprise a human CSF23’ UTR. According to certain aspects of the disclosure, the hCSF2 gene may comprise a human CSF25’ UTR, followed by a human CSF2 coding region, followed by a human CSF23’ UTR. For example, the rodent may comprise a replacement of a nucleic acid comprising the rodent’s endogenous Csf25’ UTR, endogenous Csf2 coding region, and endogenous Csf23’ UTR with a nucleic acid comprising a human CSF25’ UTR, human CSF2 coding region, and human CSF23’ UTR. The genetically modified animal may be heterozygous or homozygous for the hCSF2 gene. The genetically modified rodent may be modified in such a manner that it does not express any wild-type rodent GM-CSF polypeptide. According to certain aspects of the disclosure, there is provided a genetically modified rodent embryonic stem cell comprising one or more copies of the hCSF2 gene described herein or an embryo comprising such an embryonic stem cell (e.g., for making a genetically modified rodent comprising an hCSF2 gene as described herein). By way of example, the hCSF2 gene or the rodent, embryo, or embryonic stem cell comprising the hCSF2 gene may be any of those described in U.S. Pat. No. 8,541,646 to Stevens, et al., issued on Sep. 24, 2013, which is herein incorporated by reference in its entirety, upon which additional modifications may be made in accordance with the disclosure herein. M-CSF [00144] Macrophage colony-stimulating factor (M-CSF; NCBI Gene IDs: 1435 (homo sapiens), Gene symbol: CSF1; 12977 (mus musculus), Gene symbol: Csf1) is a cytokine that helps modulate the proliferation of monocytes, macrophages, and bone marrow progenitor cells as well as promote the differentiation of monocytes and macrophages. Expression of human or humanized M-CSF (hM-CSF) may be particularly useful for promoting the proper development and/or function of human monocytes and macrophages within a rodent. According to certain aspects of the disclosure, a rodent described herein may comprise an hCSF1 gene and/or otherwise express an hM-CSF polypeptide. The hM-CSF polypeptide may be a full-length human polypeptide (e.g., wildtype human polypeptide) or comprise a functional fragment thereof. According to certain aspects of the disclosure, the hM-CSF polypeptide may be a fully human M-CSF polypeptide. According to certain aspects of the disclosure, the mature hM-CSF polypeptide (lacking a signal peptide) may be fully human. According to certain aspects of the disclosure, the hCSF1 gene may comprise an endogenous rodent Csf15’ UTR. According to certain aspects of the disclosure, the hCSF1 gene may comprise a human CSF13’ UTR. According to certain aspects of the disclosure, the hCSF1 gene may comprise an endogenous rodent Csf15’ UTR, followed by an CSF1 coding region that encodes an M-CSF polypeptide having a fully human mature polypeptide sequence, followed by a human CSF13’ UTR. In certain instances, the rodent may be a rodent (e.g., a mouse) having an hCSF1 gene that comprises exons 2-9 of a human CSF1 gene (e.g., replacing native exons 2-9 within the endogenous rodent Csf1 locus of the genome of the genetically modified rodent). The hCSF1 gene may comprise exon 1 of an endogenous rodent Csf1 gene (e.g., the native exon within the endogenous rodent Csf1 locus of the genome of the genetically modified rodent). The genetically modified animal may be heterozygous or homozygous for the hCSF1 gene. The genetically modified rodent may be modified in such a manner that it does not express any wild-type rodent M-CSF polypeptide. According to certain aspects of the disclosure, there is provided a genetically modified rodent embryonic stem cell comprising one or more copies of the hCSF1 gene described herein or an embryo comprising such an embryonic stem cell (e.g., for making a genetically modified rodent comprising an hCSF1 gene as described herein). By way of example, the hCSF1 gene or the rodent, embryo, or embryonic stem cell comprising the hCSF1 gene may be any of those described in U.S. Pat. No. 8,847,004 to Murphy, et al., issued on Sep. 30, 2014, which is herein incorporated by reference in its entirety, upon which additional modifications may be made in accordance with the disclosure herein. TPO [00145] Thrombopoietin (TPO; NCBI Gene IDs: 7066 (homo sapiens), Gene symbol: THPO; 21832 (mus musculus), Gene symbol: Thpo) is a glycoprotein hormone produced by the liver and kidney that binds thrombopoietin receptor (c-Mpl receptor) and regulates the production of platelets via stimulating the production and differentiation of megakaryocytes. TPO supports the expansion and self-renewal of hematopoietic stem cells. Expression of human or humanized TPO (hTPO) may be particularly useful for promoting the proper development and/or function of human megakaryocytes and thrombocytes (platelets) within a rodent. According to certain aspects of the disclosure, a rodent described herein may comprise an hTPO gene and/or otherwise express an hTPO polypeptide. The hTPO polypeptide may be a full-length human polypeptide (e.g., wildtype human polypeptide) or comprise a functional fragment thereof. According to certain aspects of the disclosure, the hTPO polypeptide may be a fully human TPO polypeptide. According to certain aspects of the disclosure, the hTHPO gene may comprise an endogenous rodent Thpo 5’ UTR. According to certain aspects of the disclosure, the hTHPO gene may comprise a human THPO 3’ UTR. According to certain aspects of the disclosure, the hTHPO gene may comprise an endogenous rodent Thpo 5’ UTR, followed by a human THPO coding region, followed by a human THPO 3’ UTR. For example, the rodent may comprise a replacement of a nucleic acid comprising the rodent’s endogenous Thpo coding region and endogenous Thpo 3’ UTR with a nucleic acid comprising a human THPO coding region and human THPO 3’ UTR. The genetically modified animal may be heterozygous or homozygous for the hTHPO gene. The genetically modified rodent may be modified in such a manner that it does not express any wild-type rodent TPO polypeptide. According to certain aspects of the disclosure, there is provided a genetically modified rodent embryonic stem cell comprising one or more copies of the hTHPO gene described herein or an embryo comprising such an embryonic stem cell (e.g., for making a genetically modified rodent comprising an hTHPO gene as described herein). By way of example, the hTHPO gene or the rodent, embryo, or embryonic stem cell comprising the hTHPO gene may be any of those described in U.S. Pat. No. 9,301,509 to Stevens, et al., issued on Apr. 5, 2016, which is herein incorporated by reference in its entirety, upon which additional modifications may be made in accordance with the disclosure herein. EPO [00146] Erythropoietin (EPO; NCBI Gene IDs: 2056 (homo sapiens), Gene symbol: EPO; 13856 (mus musculus), Gene symbol: Epo) supports the development of erythroid lineage cells in the bone marrow and enhances terminal erythropoiesis. Expression of human or humanized EPO (hEPO) may be particularly useful for promoting the proper development and/or function of human erythrocytes (red blood cells) within a rodent. According to certain aspects of the disclosure, a rodent described herein may comprise an hEPO gene and/or otherwise express an hEPO polypeptide. The hEPO polypeptide may be a full-length human polypeptide (e.g., wildtype human polypeptide) or comprise a functional fragment thereof. According to certain aspects of the disclosure, the hEPO polypeptide may be a fully human EPO polypeptide. According to certain aspects of the disclosure, the hEPO gene may comprise a human EPO 5’ UTR. According to certain aspects of the disclosure, the hEPO gene may comprise an endogenous rodent Epo 3’ UTR. According to certain aspects of the disclosure, the hEPO gene may comprise an endogenous rodent Epo 5’ UTR, followed by a human EPO coding region, followed by a human EPO 3’ UTR. For example, the rodent may comprise a replacement of a nucleic acid comprising the rodent’s endogenous Epo coding region and endogenous Epo 3’ UTR with a nucleic acid comprising a human EPO coding region and a human EPO 3’ UTR. The genetically modified animal may be heterozygous or homozygous for the hEPO gene. The genetically modified rodent may be modified in such a manner that it does not express any wild- type rodent EPO polypeptide. According to certain aspects of the disclosure, there is provided a genetically modified rodent embryonic stem cell comprising one or more copies of the hEPO gene described herein or an embryo comprising such an embryonic stem cell (e.g., for making a genetically modified rodent comprising an hEPO gene as described herein). By way of example, the hEPO gene or the rodent, embryo, or embryonic stem cell comprising the hEPO gene may be any of those described in U.S. Pat. No. 9,301,509 to Stevens, et al., issued on Apr. 5, 2016, which is herein incorporated by reference in its entirety, upon which additional modifications may be made in accordance with the disclosure herein. IL-6 [00147] IL-6 (NCBI Gene IDs: 3569 (homo sapiens); Gene symbol: IL6; 16193 (mus musculus), Gene symbol: Il6) is a pleiotropic cytokine that mediates B cell differentiation and can promote T cell differentiation, activation, and proliferation, including the differentiation of T cells into cytotoxic T cells in the presence of IL-2. IL-6 is secreted by various cell types, including immune cells and cancer cells. Expression of human or humanized IL-6 (hIL-6) may be particularly useful for promoting the proper development and/or function of human T cells and, particularly, human B cells within a rodent. According to certain aspects of the disclosure, a rodent described herein may comprise an hIL6 gene and/or otherwise express an hIL-6 polypeptide. The hIL-6 polypeptide may be a full-length human polypeptide (e.g., wildtype human polypeptide) or comprise a functional fragment thereof. According to certain aspects of the disclosure, the hIL-6 polypeptide may be a fully human IL-6 polypeptide. According to certain aspects of the disclosure, the hIL6 gene may comprise an endogenous rodent Il65’ UTR. According to certain aspects of the disclosure, the hIL6 gene may comprise a human IL63’ UTR. According to certain aspects of the disclosure, the hIL6 gene may comprise an endogenous rodent Il65’ UTR, followed by a human IL6 coding region, followed by a human IL63’ UTR. For example, the rodent may comprise a replacement of a nucleic acid comprising the rodent’s endogenous Il6 coding region and endogenous Il63’ UTR with a nucleic acid comprising a human IL6 coding region and human IL63’ UTR. The genetically modified animal may be heterozygous or homozygous for the hIL6 gene. The genetically modified rodent may be modified in such a manner that it does not express any wild-type rodent IL-6 polypeptide. According to certain aspects of the disclosure, there is provided a genetically modified rodent embryonic stem cell comprising one or more copies of the hIL6 gene described herein or an embryo comprising such an embryonic stem cell (e.g., for making a genetically modified rodent comprising an hIL-6 gene as described herein). By way of example, the hIL6 gene or the rodent, embryo, or embryonic stem cell comprising the hIL6 gene may be any of those described in U.S. Pat. No. 8,878,001 to Wang, et al., issued on May 9, 2013, which is herein incorporated by reference in its entirety, upon which additional modifications may be made in accordance with the disclosure herein. IL-6Rα [00148] IL-6 receptor is the receptor for IL-6 and is expressed in activated B cells and resting T cells. The IL6 receptor is a protein complex consisting of an IL-6 receptor subunit (IL6Rα; NCBI Gene IDs: 3570 (homo sapiens), Gene symbol: IL6R; 16194 (mus musculus), Gene symbol: Il6ra) and interleukin 6 signal transducer Glycoprotein 130. Expression of human or humanized IL-6Rα (hIL-6Rα) may be particularly useful for studying the effects of human IL- 6 in rodents that comprise human IL-6 secreting cells (e.g., transplanted human immune or cancer cells) and/or for preserving proper IL-6/IL-6 receptor signaling within rodents that express hIL-6, especially those which do not express endogenous wildtype IL-6. According to certain aspects of the disclosure, a rodent described herein may comprise an hIL6R gene and/or otherwise express an hIL-6Rα polypeptide. The hIL-6Rα polypeptide may be a full-length human polypeptide (e.g., wildtype human polypeptide) or comprise a functional fragment thereof. According to certain aspects of the disclosure, the hIL-6Rα polypeptide may be a fully human IL-6Rα polypeptide. According to certain aspects of the disclosure, the hIL-6Rα polypeptide comprises a human extracellular domain (e.g., the extracellular portion of a human IL-6Rα protein). For example, the hIL-6Rα polypeptide may comprise the coding portion of human exon 1 (beginning at the start codon, ATG) through human exon 8. According to certain aspects of the disclosure, a rodent may express a humanized (chimeric) IL-6Rα polypeptide. For example, the humanized IL-6Rα polypeptide may comprise a human extracellular domain and an endogenous rodent (e.g., mouse) intracellular domain (e.g., the intracellular portion of a rodent IL-6Rα protein). The chimeric polypeptide may be a rodent IL-6Rα polypeptide having its extracellular domain, or a substantial portion thereof, replaced with a human IL-6Rα extracellular domain. In certain instances, the rodent may be a rodent (e.g., a mouse) having an hIL6R gene that comprises the coding portion of human exon 1 (beginning at the start codon, ATG) through human exon 8 of a human IL6R gene (e.g., replacing the coding portion of the endogenous rodent exon 1 through the endogenous exon 8 within the endogenous rodent Il6ra locus of the genome of the genetically modified rodent). The hIL6R gene may comprise an endogenous rodent Il6ra 5’ UTR, endogenous exons 9 and 10 of an endogenous rodent Il6ra gene, and an endogenous Il6ra 3’ UTR (e.g., the native UTRs and native exons 9 and 10 within the endogenous rodent Il6ra locus of the genome of the genetically modified rodent). The genetically modified animal may be heterozygous or homozygous for the hIL6R gene. The genetically modified rodent may be modified in such a manner that it does not express any wild- type rodent IL-6Rα polypeptide. According to certain aspects of the disclosure, there is provided a genetically modified rodent embryonic stem cell comprising one or more copies of the hIL6R gene described herein or an embryo comprising such an embryonic stem cell (e.g., for making a genetically modified rodent comprising an hIL6R gene as described herein). By way of example, the hIL6R gene or the rodent, embryo, or embryonic stem cell comprising the hIL6R gene may be any of those described in U.S. Pat. No. 9,125,386 to Wang, et al., issued on Sep. 8, 2015, which is herein incorporated by reference in its entirety, upon which additional modifications may be made in accordance with the disclosure herein. IL-7 [00149] IL-7 (NCBI Gene ID: 3574 (homo sapiens), Gene symbol: IL7; 16196 (mus musculus), Gene symbol: Il7) is a cytokine that promotes the differentiation of lymphoid progenitor cells and the proliferation of lymphoid lineage cells. It is essential for development of immature B and T cells and, to some degree, mature T cells. IL-7 is produced by epithelial cells in the thymus and intestine, in keratinocytes, liver, and dendritic cells-but not by normal lymphocytes. Expression of human or humanized IL-7 (hIL-7) may be particularly useful for promoting the proper development and/or function of human lymphocytes, particularly B cells and T cells, within a rodent. According to certain aspects of the disclosure, a rodent described herein may comprise an hIL7 gene and/or otherwise express an hIL-7 polypeptide. The hIL-7 polypeptide may be a full-length human polypeptide (e.g., wildtype human polypeptide) or comprise a functional fragment thereof. According to certain aspects of the disclosure, the hIL-7 polypeptide may be a fully human IL-7 polypeptide. According to certain aspects of the disclosure, the mature hIL-7 polypeptide (lacking a signal peptide) may be fully human. According to certain aspects of the disclosure, the hIL7 gene may comprise an endogenous rodent Il75’ UTR. According to certain aspects of the disclosure, the hIL7 gene may comprise a human IL73’ UTR. According to certain aspects of the disclosure, the hIL7 gene may comprise an endogenous rodent Il75’ UTR, followed by an IL7 coding region that encodes an IL-7 polypeptide having a fully human mature polypeptide sequence, followed by a human IL73’ UTR. In certain instances, the rodent may be a rodent (e.g., a mouse) having an hIL7 gene that comprises exons 2-6 of a human IL7 gene (e.g., replacing native exons 2-5 within the endogenous rodent Il7 locus of the genome of the genetically modified rodent). The hIL7 gene may comprise exon 1 of an endogenous rodent Il7 gene (e.g., the native exon within the endogenous rodent Il7 locus of the genome of the genetically modified rodent). The genetically modified animal may be heterozygous or homozygous for the hIL7 gene. The genetically modified rodent may be modified in such a manner that it does not express any wild-type rodent IL-7 polypeptide. According to certain aspects of the disclosure, there is provided a genetically modified rodent embryonic stem cell comprising one or more copies of the hIL7 gene described herein or an embryo comprising such an embryonic stem cell (e.g., for making a genetically modified rodent comprising an hIL7 gene as described herein). By way of example, the hIL7 gene or the rodent, embryo, or embryonic stem cell comprising the hIL7 gene may be any of those described in U.S. Pat. No. 8,962,913 to Murphy, issued on Feb. 24, 2015, which is herein incorporated by reference in its entirety, upon which additional modifications may be made in accordance with the disclosure herein. BAFF [00150] B-cell activating factor (BAFF; NCBI Gene IDs: 10673 (homo sapiens), Gene symbol: TNFSF13B; 24099 (mus musculus), Gene symbol: Tnfsf13b) is a member of the tumor necrosis factor (TNF) ligand superfamily and is expressed by many different cell types, including astrocytes, B cell lineage cells, dendritic cells, monocytes, neutrophils and stromal cells. It is expressed as a Type II transmembrane protein and can be released in soluble form via cleavage at a furin consensus site after proteolysis. Reported receptors for BAFF include, most notably, BAFF receptor (BAFF-R), but also include transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B cell maturation antigen (BCMA). BAFF plays a role in B cell activation and development. Expression of human or humanized BAFF (hBAFF) may be particularly useful for promoting the development and long-term survival of human B cells in rodents, including antigen-specific B cells (e.g., in immunized animals engrafted with human HSCs), and adoptively transferred mature B cells. According to certain aspects of the disclosure, a rodent described herein may comprise an hTNFSF13B gene and/or otherwise express an hBAFF polypeptide. The hBAFF polypeptide may be a full-length human polypeptide (e.g., wildtype human polypeptide) or comprise a functional fragment thereof. According to certain aspects of the disclosure, the hBAFF polypeptide may be a fully human BAFF polypeptide. According to certain aspects of the disclosure, the hBAFF polypeptide comprises a human extracellular domain (e.g., the extracellular portion of a human BAFF protein). For example, the hBAFF polypeptide may comprise residues 142-285 of the amino acid sequence set forth in NCBI Ref Seq: NP_006564.1, which is herein incorporated by reference in its entirety, or comprise an amino acid sequence that is substantially identical (e.g., at least 90, 95, 96, 97, 98, or 99% identical) to residues 142-285. According to certain aspects of the disclosure, a rodent may express a humanized (chimeric) BAFF polypeptide. For example, the humanized BAFF polypeptide may comprise a human extracellular domain and an endogenous rodent (e.g., mouse) intracellular domain (e.g., the intracellular portion of a rodent BAFF protein). The chimeric polypeptide may be a rodent BAFF polypeptide having its extracellular domain, or a substantial portion thereof, replaced with a human BAFF extracellular domain. In certain instances, the rodent may be a rodent (e.g., a mouse) having an hTNFSF13B gene that comprises exons 3-6 of a human TNFSF13B gene (e.g., replacing a nucleic acid sequence comprising native exons 3-7 or native exons 3-6 as well as the coding portion of native exon 7 within the endogenous rodent Tnfsf13b locus of the genome of the genetically modified rodent). The hTNFSF13B gene may comprise a 3’ portion of intron 2 of a human TNFSF13B gene (e.g., replacing a 3’ portion of native intron 2 within the endogenous rodent Tnfsf13b locus of the genome of the genetically modified rodent). The hTNFSF13B gene may comprise exons 1 and 2 of an endogenous rodent Tnfsf13b gene (e.g., the native exons within the endogenous rodent Tnfsf13b locus of the genome of the genetically modified rodent). The hTNFSF13B gene may comprise a 5’ portion of intron 2 of an endogenous rodent Tnfsf13b gene (e.g., a 5’ portion of the native intron 2 within the endogenous rodent Tnfsf13b locus of the genome of the genetically modified rodent). The 5’ portion may comprise a splice donor site. The hTNFSF13B gene may comprise a 3’ portion of exon 7 of an endogenous rodent Tnfsf13b gene (e.g., a 3’ portion of the native exon 7 within the endogenous rodent Tnfsf13b locus of the genome of the genetically modified rodent). The 3’ portion of endogenous exon 7 may comprise an endogenous Tnfsf13b 3’ UTR. In some instances, the hTNFSF13B gene may comprise exons 1 and 2 of an endogenous rodent Tnfsf13b gene (e.g., exon 1 through a 5’ portion of intron 2), followed by exons 3-6 of a human TNFSF13B gene (e.g., a 3’ portion of intron 2 through exon 6, including a human TNFSF13B 3’ UTR), followed by a 3’ portion of exon 7 of an endogenous rodent Tnfsf13b gene (including an endogenous Tnfsf13b 3’ UTR). The genetically modified animal may be heterozygous or homozygous for the hTNFSF13B gene. The genetically modified rodent may be modified in such a manner that it does not express any wild-type rodent BAFF polypeptide. According to certain aspects of the disclosure, there is provided a genetically modified rodent embryonic stem cell comprising one or more copies of the hTNFSF13B gene described herein or an embryo comprising such an embryonic stem cell (e.g., for making a genetically modified rodent comprising an hTNFSF13B gene as described herein). By way of example, the hTNFSF13B gene or the rodent, embryo, or embryonic stem cell comprising the hTNFSF13B gene may be any of those described in U.S. Pat. No. 9,629,347 to McWhirter, et al., issued on Apr. 25, 2017, which is herein incorporated by reference in its entirety, upon which additional modifications may be made in accordance with the disclosure herein. APRIL [00151] A proliferation-inducing ligand (APRIL; NCBI Gene IDs: 8741 (homo sapiens), Gene symbol: TNFSF13; 69583 (mus musculus), Gene symbol: Tnfsf13) is a member of the tumor necrosis factor (TNF) ligand superfamily and is expressed by many different cell types, including dendritic cells, epithelial cells, macrophages, monocytes, osteoclasts and T cells. It is expressed as a Type II transmembrane protein and can be released in soluble form via cleavage at a furin consensus site after proteolysis. Reported receptors for APRIL include transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B cell maturation antigen (BCMA). APRIL plays a role in B cell and T cell activation and survival, and, notably, stimulates the growth of tumor cells in vitro and in vivo. Expression of human or humanized APRIL (hAPRIL) may be particularly useful for promoting the development and long-term survival of human B cells in rodents, including antigen-specific B cells (e.g., in immunized animals engrafted with human HSCs), and adoptively transferred mature B cells. According to certain aspects of the disclosure, a rodent described herein may comprise an hTNFSF13 gene and/or otherwise express an hAPRIL polypeptide. The hAPRIL polypeptide may be a full-length human polypeptide (e.g., wildtype human polypeptide) or comprise a functional fragment thereof. According to certain aspects of the disclosure, the hAPRIL polypeptide may be a fully human APRIL polypeptide. According to certain aspects of the disclosure, the hAPRIL polypeptide comprises a human extracellular domain (e.g., the extracellular portion of a human APRIL protein). For example, the hAPRIL polypeptide may comprise residues 87-250 of the amino acid sequence set forth in NCBI Ref Seq: NP_003799.1, which is herein incorporated by reference in its entirety, or comprise an amino acid sequence that is substantially identical (e.g., at least 90, 95, 96, 97, 98, or 99% identical) to residues 87-250. According to certain aspects of the disclosure, a rodent may express a humanized (chimeric) APRIL polypeptide. For example, the humanized APRIL polypeptide may comprise a human extracellular domain and an endogenous rodent (e.g., mouse) intracellular domain (e.g., the intracellular portion of a rodent APRIL protein). The chimeric polypeptide may be a rodent APRIL polypeptide having its extracellular domain, or a substantial portion thereof, replaced with a human APRIL extracellular domain. In certain instances, the rodent may be a rodent (e.g., a mouse) having an hTNFSF13 gene that comprises exons 2-6 of a human TNFSF13 gene (e.g., replacing a nucleic acid sequence comprising native exons 2-6 or native exons 2-5 as well as the coding portion of native exon 6 within the endogenous rodent Tnfsf13 locus of the genome of the genetically modified rodent). The hTNFSF13 gene may comprise a 3’ portion of intron 1 of a human TNFSF13 gene (e.g., replacing a 3’ portion of native intron 1 within the endogenous rodent Tnfsf13 locus of the genome of the genetically modified rodent). The hTNFSF13 gene may comprise exon 1 of an endogenous rodent Tnfsf13 gene (e.g., the native exon within the endogenous rodent Tnfsf13 locus of the genome of the genetically modified rodent). The hTNFSF13 gene may comprise a 5’ portion of intron 1 of an endogenous rodent Tnfsf13 gene (e.g., a 5’ portion of the native intron 1 within the endogenous rodent Tnfsf13 locus of the genome of the genetically modified rodent). The 5’ portion may comprise a splice donor site. The hTNFSF13 gene may comprise a 3’ portion of exon 6 of an endogenous rodent Tnfsf13 gene (e.g., a 3’ portion of the native exon 6 within the endogenous rodent Tnfsf13 locus of the genome of the genetically modified rodent). The 3’ portion of endogenous exon 6 may comprise an endogenous Tnfsf133’ UTR. In some instances, the hTNFSF13 gene may comprise exon 1 of an endogenous rodent Tnfsf13 gene (e.g., exon 1 through a 5’ portion of intron 1), followed by exons 2-6 of a human TNFSF13 gene (e.g., a 3’ portion of intron 1 through exon 6, including a human TNFSF133’ UTR), followed by a 3’ portion of exon 6 of an endogenous rodent Tnfsf13 gene (including an endogenous Tnfsf133’ UTR). The genetically modified animal may be heterozygous or homozygous for the hTNFSF13 gene. The genetically modified rodent may be modified in such a manner that it does not express any wild-type rodent APRIL polypeptide. According to certain aspects of the disclosure, there is provided a genetically modified rodent embryonic stem cell comprising one or more copies of the hTNFSF13 gene described herein or an embryo comprising such an embryonic stem cell (e.g., for making a genetically modified rodent comprising an hTNFSF13 gene as described herein). By way of example, the hTNFSF13 gene or the rodent, embryo, or embryonic stem cell comprising the hTNFSF13 gene may be any of those described in U.S. Pat. No. 9,730,435 to McWhirter, et al., issued on Aug. 15, 2017, which is herein incorporated by reference in its entirety, upon which additional modifications may be made in accordance with the disclosure herein. CXCL13 [00152] C-X-C motif chemokine ligand 13 (CXCL13; NCBI Gene IDs: 10563 (homo sapiens), Gene symbol: CXCL13; 55985 (mus musculus), Gene symbol: Cxcl13) is a protein ligand selectively chemotactic for B cells and follicular B helper T cells (TFH cells) that elicits its effects by interacting with chemokine receptor CXCR5. CXCL13 is strongly expressed in the liver, spleen, lymph nodes, and Peyer's patches and is believed to be a critical chemokine for attracting B cells and TFH cells to the germinal center for B cell activation, class switching, and somatic hyper-mutation. Expression of human or humanized CXCL13 (hCXCL13) may be particularly useful for promoting the development and long-term survival of human B cells in rodents, including antigen-specific B cells (e.g., in immunized animals engrafted with human HSCs), and adoptively transferred mature B cells, as well as for engrafting cancer or tumor cells, such as lymphocytic leukemia cells (e.g., CLL or ALL). According to certain aspects of the disclosure, a rodent described herein may comprise an hCXCL13 gene and/or otherwise express an hCXCL13 polypeptide. The hCXCL13 polypeptide may be a full-length human polypeptide (e.g., wildtype human polypeptide) or comprise a functional fragment thereof. According to certain aspects of the disclosure, the hCXCL13 polypeptide may be a fully human CXCL13 polypeptide. According to certain aspects of the disclosure, the hCXCL13 polypeptide comprises a human chemokine IL-8 like domain (e.g., the chemokine IL-8 like domain of a human CXCL13 protein). For example, the hCXCL13 polypeptide may comprise residues 30-91 of the amino acid sequence set forth in NCBI Ref Seq: NP_006410.1, which is herein incorporated by reference in its entirety, or comprise an amino acid sequence that is substantially identical (e.g., at least 90, 95, 96, 97, 98, or 99% identical) to residues 30-91. According to certain aspects of the disclosure, a rodent may express a humanized (chimeric) CXCL13 polypeptide. The chimeric polypeptide may be a rodent CD47 polypeptide having its chemokine IL-8 like domain, or a substantial portion thereof, replaced with a human CXCL13 chemokine IL-8 like domain. In certain instances, the rodent may be a rodent (e.g., a mouse) having an hCXCL13 gene that comprises exons 3 and 4 of a human CXCL13 gene (e.g., replacing a nucleic acid sequence comprising native exons 2 and 3 within the endogenous rodent Cxcl13 locus of the genome of the genetically modified rodent). In certain instances, the rodent may be a rodent (e.g., a mouse) having an hCXCL13 gene that comprises exons 3-5 of a human CXCL13 gene (e.g., replacing a nucleic acid sequence comprising native exons 2-4 or native exons 2 and 3 as well as the coding portion of native exon 4 within the endogenous rodent Cxcl13 locus of the genome of the genetically modified rodent). The hCXCL13 gene may comprise a 3’ portion of intron 2 of a human CXCL13 gene (e.g., replacing a 3’ portion of native intron 1 within the endogenous rodent Cxcl13 locus of the genome of the genetically modified rodent). The hCXCL13 may comprise an endogenous rodent Cxcl13 signal peptide-encoding sequence (e.g., the native signal peptide-encoding sequence within the endogenous Cxcl13 locus of the genome of the genetically modified rodent). The hCXCL13 gene may comprise exon 1 of an endogenous rodent Cxcl13 gene (e.g., the native exon within the endogenous rodent Cxcl13 locus of the genome of the genetically modified rodent). The hCXCL13 gene may comprise a 5’ portion of intron 1 of an endogenous rodent Cxcl13 gene (e.g., a 5’ portion of the native intron 1 within the endogenous rodent Cxcl13 locus of the genome of the genetically modified rodent). The 5’ portion may comprise a splice donor site. The hCXCL13 gene may comprise a 3’ portion of exon 4 of an endogenous rodent Cxcl13 gene (e.g., a 3’ portion of the native exon 4 within the endogenous rodent Cxcl13 locus of the genome of the genetically modified rodent). The 3’ portion of endogenous exon 4 may comprise an endogenous Cxcl133’ UTR. In some instances, the hCXCL13 gene may comprise exon 1 of an endogenous rodent Cxcl13 gene (e.g., exon 1 through a 5’ portion of intron 1), followed by exons 3-5 of a human CXCL13 gene (e.g., a 3’ portion of intron 2 through exon 5, including a human CXCL133’ UTR), followed by a 3’ portion of exon 4 of an endogenous rodent Cxcl13 gene (including an endogenous Cxcl133’ UTR). The genetically modified animal may be heterozygous or homozygous for the hCXCL13 gene. The genetically modified rodent may be modified in such a manner that it does not express any wild- type rodent CXCL13 polypeptide. According to certain aspects of the disclosure, there is provided a genetically modified rodent embryonic stem cell comprising one or more copies of the hCXCL13 gene described herein or an embryo comprising such an embryonic stem cell (e.g., for making a genetically modified rodent comprising an hCXCL13 gene as described herein). By way of example, the hCXCL13 gene or the rodent, embryo, or embryonic stem cell comprising the hCXCL13 gene may be any of those described in U.S. Pat. App. Pub. No. US 2023-0172170 to Frleta, et al., published on June 8, 2023, which is herein incorporated by reference in its entirety, upon which additional modifications may be made in accordance with the disclosure herein. HMOX-1 [00153] Heme oxygenase (HMOX) metabolizes heme and releases free iron, carbon monoxide, and biliverdin, which quickly undergoes conversion to bilirubin. Humans and mice contain two well-characterized heme oxygenase enzymes: HMOX-1 (NCBI Gene IDs: 3162 (homo sapiens), Gene symbol: HMOX1; 15368 (mus musculus), Gene symbol: Hmox1), which is inducible, and HMOX-2, which is constitutively expressed in most tissues. Hmox1-/- mice have decreased macrophages (F4/80+) in spleen, liver, blood and bone marrow (BM), but still have myeloid cells (CD11b+). Lack of HMOX-1 renders erthyrophagocytic macrophages unable to process heme and causes intracellular toxicity due to heme build-up. Knockout of endogenous Hmox1 in rodents, such as rodents (e.g., mice), may be particularly useful for promoting the survival and development of human red blood cells (RBCs) and human RBC progenitors. According to certain aspects of the disclosure, the genetically modified rodent may comprise a null mutation in the rodent Hmox1 gene at the rodent Hmox1 gene locus. The null mutation comprises a deletion, an insertion, and/or a substitution in the rodent Hmox1 gene at the rodent Hmox1 gene locus. In some such instances, the endogenous rodent Hmox1 locus comprises a null mutation, and hence, a null allele. A null allele is a mutant copy of a gene that completely lacks that gene’s normal function. This can be the result of the complete absence of the gene product (protein, RNA) at the molecular level, or the expression of a non-functional gene product. At the phenotypic level, a null allele is indistinguishable from a deletion of the entire locus. In certain instances, the rodent may be a rodent (e.g., a mouse) having an Hmox1 null mutation that is a deletion of at least exons 3-5. In some instances, the null mutation is a deletion of the full Hmox1 endogenous coding sequence. The rodent may comprise the same null mutation for all the alleles. The rodent may comprise different null mutations for different alleles. Mouse Hmox1 is located on Chromosome 8, GRCm39, NC_000074.7 (75820246-75827221), and the mouse Hmox1 coding sequence may be found at Genbank Accession No. NM_010442.2. The mouse Hmox1 locus includes 5 exons, with exons 1-5 being coding exons. As such, the genetically modified animals provided herein may be mice, and one or more of exons 1-5 of the mouse Hmox1 gene may be deleted or mutated in the genetically modified mice. In some instances, other aspects of the genomic locus of the mouse Hmox1 gene, e.g., introns, 3' and/or 5' untranslated sequence (UTRs) are also deleted or mutated. In some instances, the whole regions of the mouse Hmox1 genomic locus are deleted. In some instances, the whole genomic region from the start codon to the stop codon of the mouse Hmox1 gene is deleted. For example, the genetically modified mice may comprise a deletion of ~7 kb of mouse sequence (GRCm38 coordinates chr8: 75093750- 75100019). The deleted, modified or altered Hmox1 gene at the endogenous Hmox1 locus can be detected using a variety of methods including, for example, PCR, Western blot, Southern blot, restriction fragment length polymorphism (RFLP), or a gain or loss of allele assay. The genetically modified animal may be heterozygous or homozygous for the endogenous Hmox1 null mutation. The genetically modified rodent may be modified in such a manner that it does not express any wild-type rodent HMOX-1 polypeptide (e.g., in a rodent homozygous for the endogenous Hmox1 null allele). According to certain aspects of the disclosure, there is provided a genetically modified rodent embryonic stem cell comprising one or more copies of the Hmox1 null mutation/allele described herein or an embryo comprising such an embryonic stem cell (e.g., for making a genetically modified rodent comprising an endogenous Hmox1 null mutation/allele as described herein). By way of example, the endogenous Hmox1 null mutation/allele or the rodent, embryo, or embryonic stem cell comprising the endogenous Hmox1 null mutation may be any of those described in PCT App. Pub. No. WO 2024/020057 to Frleta, et al., published on Jan. 25, 2024, which is herein incorporated by reference in its entirety, upon which additional modifications may be made in accordance with the disclosure herein. Combinations of Modifications [00154] Provided herein are genetically modified rodents engrafted with human cells in accordance with the methods described herein. In some embodiments, provided are genetically modified rodent that are or have been engrafted with a human cell population and/or by methods as described herein. [00155] In some embodiments, engrafted rodents or rodents for engraftment (e.g., mice or rats) provided herein comprise a Recombination-activating gene 2 (Rag2) gene knock-out and/or an Interleukin 2 receptor gamma (Il2rg) gene knock-out. In some embodiments, engrafted rodents or rodents for engraftment further comprise a human or humanized signal regulatory protein alpha (SIRPA) knock-in. In some embodiments, an engrafted rodent or rodent for engraftment comprises a Rag2 gene knock-out, an Il2rg gene knock-out, and a human or humanized SIRPA knock-in. In some embodiments, engrafted rodents or rodents for engraftment (e.g., mice or rats) provided herein are Rag2-/-; Il2rγ-/-; SIRPAh/h. In some embodiments, an engrafted rodent or rodent for engraftment comprises a Rag2 gene knock-out, an Il2rg gene knock-out, a human or humanized SIRPA knock-in, and one or more additional modifications. In some embodiments, a genetically modified rodent of the present disclosure comprises, in its genome: (i) a human or humanized SIRPA gene, (ii) a homozygous knockout mutation of an endogenous Rag, e.g., endogenous Rag2, gene, and (iii) a homozygous knockout mutation of an endogenous Il2r, e.g., endogenous Il2rγ, gene. In other embodiments, a genetically modified rodent of the present disclosure comprises, in its genome: (i) a human or humanized SIRPA gene, (ii) a human or humanized Il15 gene, (iii) a homozygous knockout mutation of an endogenous Rag, e.g., endogenous Rag2, gene, and (iv) a homozygous knockout mutation of an endogenous Il2r, e.g., endogenous Il2rγ, gene. Such a genetically modified rodent can be further genetically modified, e.g., to comprise one or more human or humanized component of the immune system, e.g., to comprise a human or humanized MHC molecule as described herein. [00156] Accordingly, in some embodiments, a genetically modified rodent as described herein comprises, in its genome: (i) a nucleotide sequence, e.g., recombinant nucleic acid, encoding (at least) an antigen presenting portion of a human or humanized MHC, e.g., classical HLA, molecule, (ii) a human or humanized SIRPA gene, (iii) a homozygous knockout mutation of an endogenous Rag, e.g., endogenous Rag2, gene, and (iv) a homozygous knockout mutation of an endogenous Il2r, e.g., endogenous Il2rγ, gene. In other embodiments, a genetically modified rodent of the present disclosure comprises, in its genome: (i) a nucleotide sequence, e.g., recombinant nucleic acid, encoding (at least) an antigen presenting portion of a human or humanized MHC, e.g., classical HLA, molecule, (ii) a human or humanized SIRPA gene, (iii) a human or humanized IL15 gene, (iv) a homozygous knockout mutation of an endogenous Rag, e.g., endogenous Rag2, gene, and (v) a homozygous knockout mutation of an endogenous Il2r, e.g., endogenous Il2rγ, gene. [00157] Such a genetically modified rodent may also be particularly useful for the adoptive transfer of human T cells, e.g., genetically modified or engineered T cells expressing (at least) a human TCR variable domain, as described herein. Accordingly, in some embodiments, the genetically modified rodent of the present invention comprises: (a) in its genome, (i) a first recombinant nucleic acid encoding (at least) an antigen presenting portion of a human or humanized MHC, e.g., classical HLA, molecule, (ii) a human or humanized SIRPA gene, (iii) a homozygous knockout mutation of an endogenous Rag, e.g., endogenous Rag2, gene, and (iv) a homozygous knockout mutation of an endogenous Il2r, e.g., endogenous Il2rγ, gene, and (b) in its periphery, a human T cell, wherein the human T cell is genetically modified to express a second recombinant nucleic acid that encodes (at least) a recombinant human T cell receptor (TCR) variable domain, optionally wherein the human T cell expresses the recombinant human TCR variable domain on its cell surface, and optionally wherein the recombinant human TCR variable domain binds an antigen presented in the context of the antigen presenting portion of the human or humanized MHC, e.g., classical HLA, molecule. In some embodiments, the genetically modified rodent further comprises, in its genome, a human or humanized IL-15 gene. [00158] In specific embodiments, the genetically modified rodent of the present invention comprises: (a) in its genome, (i) a first recombinant nucleic acid, wherein the first recombinant nucleic acid encodes at least the α1, α2, β1, and β2 domains of a classical HLA-DQ2.5 class II molecule, (ii) a human or humanized SIRPA gene, (iii) a human or humanized IL15 gene, (iv) a homozygous knockout mutation of an endogenous Rag2 gene, and (v) a homozygous knockout mutation of an endogenous Il2rγ gene; and (b) in its periphery, a human T cell genetically modified to express a second recombinant nucleic acid that encodes (at least) a recombinant human TCR variable domain, wherein the human T cell expresses the recombinant human TCR variable domain on its cell surface, and wherein the recombinant human TCR variable domain recognizes gliadin presented in the context of the α1, α2, β1, and β2 domains of the classical HLA-DQ2.5 class II molecule. In some embodiments, the genetically modified rodent further comprises, in its genome, a human or humanized IL15 gene. Methods of Making [00159] Provided herein are also methods of making the genetically modified rodents as described herein. In various embodiments, the method of making the genetically modified rodent as described herein comprises introducing a human T cell, e.g., an engineered human T cell, into the genetically modified rodent as described herein (e.g., a genetically modified rodent expressing at least an antigen presenting portion of a classical HLA molecule, and optionally, one or more genetic modifications that enhance the adoptive transfer of human cell, e.g., human T cells). In some embodiments, an engineered human T cell as described herein expresses a recombinant nucleic acid that encodes (at least) a recombinant human TCR variable domain. In some embodiments, an engineered human T cell as described herein expresses a recombinant nucleic acid that encodes (at least) a recombinant human TCR α variable domain and (at least) a recombinant human TCR β variable domain. In some embodiments, an engineered human T cell as described herein expresses a recombinant nucleic acid that encodes a recombinant human TCR, i.e., variable and constant domains of the TCR α and β chains. In some embodiments, the recombinant human TCR variable domain binds an antigen presented in the context of the antigen presenting portion of the human or humanized MHC, e.g., classical HLA, molecule of the genetically modified rodent. In some embodiments, the recombinant human TCR is MHC- restricted, e.g., HLA-restricted, e.g., HLA-DQ2.5-restricted. In some embodiments, the recombinant human TCR is antigen-specific, e.g., gliadin-specific, e.g., α1 gliadin-specific. In some embodiments, the recombinant human TCR variable domain is an HLA-restricted antigen- specific, e.g., HLA-DQ2.5-restricted ⍺1-gliadin-specific, TCR variable domain. In some embodiments, the engineered T cell does not express endogenous TCR genes. [00160] Accordingly, in various embodiments, a method of making the genetically modified rodent as described herein comprises introducing a human T cell into a genetically modified rodent as described herein (e.g., comprising in its genome a first recombinant nucleic acid encoding at least an antigen presenting portion of a classical HLA molecule and one or more genetic modifications that enhance the adoptive transfer of human cell, e.g., human T cells), wherein the human T cell expresses a second recombinant nucleic acid that encodes (at least) a recombinant human TCR variable domain that binds an antigen presented in the context of the antigen presenting portion of the classical HLA molecule. [00161] In some embodiments, generating a genetically modified rodent as described herein may comprise breeding, e.g., mating, animals of the same species. In other embodiments, generating a genetically modified rodent as described herein may comprise sequential homologous recombination in ES cells. In some embodiments, the ES cells are derived from rodents genetically modified to comprise one or more, but not all, of the genetic modifications desired, and homologous recombination in such ES cells completes the genetic modification. In other embodiments, generating a genetically modified rodent as described herein may comprise a combination of breeding and homologous recombination in ES cells, e.g., breeding an rodent to another rodent, wherein some or all of the rodents may be generated from ES cells genetically modified via a single homologous recombination or sequential homologous recombination events, and wherein some ES cell may be isolated from a rodent comprising one or more of the genetic modifications disclosed herein. [00162] In some embodiments, the method utilizes a targeting construct made using VELOCIGENE® technology, introducing the construct into ES cells, and introducing targeted ES cell clones into a mouse embryo using VELOCIMOUSE® technology, as described in the Examples. Targeting constructs may comprise 5’ and/or 3’ homology arms that target the endogenous sequence to be replaced, an insert sequence (that replaces the endogenous sequence) and one or more selection cassettes. A selection cassette is a nucleotide sequence inserted into a targeting construct to facilitate selection of cells (e.g., ES cells) that have integrated the construct of interest. A number of suitable selection cassettes are known in the art. Commonly, a selection cassette enables positive selection in the presence of a particular antibiotic (e.g., Neo, Hyg, Pur, CM, SPEC, etc.). In addition, a selection cassette may be flanked by recombination sites, which allow deletion of the selection cassette upon treatment with recombinase enzymes. Commonly used recombination sites are loxP and Frt, recognized by Cre and Flp enzymes, respectively, but others are known in the art. A selection cassette may be located anywhere in the construct outside the coding region. In one embodiment, the selection cassette is located at the 5’ end the human DNA fragment. In another embodiment, the selection cassette is located at the 3’ end of the human DNA fragment. In another embodiment, the selection cassette is located within the human DNA fragment. In another embodiment, the selection cassette is located within an intron of the human DNA fragment. In another embodiment, the selection cassette is located at the junction of the human and mouse DNA fragment. [00163] Upon completion of gene targeting, ES cells or genetically modified non-human animals are screened to confirm successful incorporation of exogenous nucleotide sequence of interest or expression of exogenous polypeptide. Numerous techniques are known to those skilled in the art, and include (but are not limited to) Southern blotting, long PCR, quantitative PCR (e.g., real-time PCR using TAQMAN®), fluorescence in situ hybridization, Northern blotting, flow cytometry, Western analysis, immunocytochemistry, immunohistochemistry, etc. In one example, non-human animals (e.g., mice) bearing the genetic modification of interest can be identified by screening for loss of mouse allele and/or gain of human allele using a modification of allele assay described in Valenzuela et al. (2003) High-throughput engineering of the mouse genome coupled with high-resolution expression analysis, Nature Biotech. 21(6):652- 659. Other assays that identify a specific nucleotide or amino acid sequence in the genetically modified animals are known to those skilled in the art. [00164] Accordingly, in some embodiments the method comprises: (a) genetically modifying a rodent embryonic stem (ES) cell to comprise a recombinant nucleic acid encoding (at least) an antigen presenting portion of a classical HLA molecule, and optionally one or more additional genetic modifications as described herein, e.g., one or more genetic modifications that enhance the adoptive transfer of human cell, e.g., human T cells, (b) introducing the genetically modified rodent ES cell into a rodent host embryo, (c) implanting and gestating the rodent host embryo in a surrogate mother to produce the genetically modified rodent, and (d) introducing into the genetically modified rodent a human T cell that expresses a second recombinant nucleic acid that encodes (at least) a recombinant human TCR variable domain that binds an antigen presented in the context of the antigen presenting portion of the classical HLA molecule. [00165] In additional embodiments, the method comprises: (a) breeding a genetically modified rodent comprising a recombinant nucleic acid encoding (at least) an antigen presenting portion of a classical HLA molecule with a genetically modified rodent comprising one or more additional genetic modifications as described herein, e.g., one or more genetic modifications that enhance the adoptive transfer of human cell, e.g., human T cells, such that the resulting progeny comprise a recombinant nucleic acid encoding (at least) an antigen presenting portion of a classical HLA molecule and one or more additional genetic modifications as described herein, and (b) introducing into the genetically modified rodent a genetically modified human T cell that expresses a second recombinant nucleic acid that encodes (at least) a recombinant human TCR variable domain that binds an antigen presented in the context of the antigen presenting portion of the classical HLA molecule. Methods of Use [00166] Further provided herein are methods of using the genetically modified rodents as described herein. [00167] Accordingly, provided herein are methods of determining the pathogenesis of an antigen. In some embodiments, the method comprises administering an antigen to a genetically modified rodent as described herein and determining the absence or presence of activated human T cells in the genetically modified rodent. In some embodiments, the presence of activated human T cells in the genetically modified rodent indicates the antigen is pathogenic. In some embodiments, administering comprises oral gavage with a gliadin peptide. [00168] The term “administration” and the like refers to and includes the administration of a composition to a subject or system (e.g., to a cell, organ, tissue, organism, or relevant component or set of components thereof). The skilled artisan will appreciate that route of administration may vary depending, for example, on the subject or system to which the composition is being administered, the nature of the composition, the purpose of the administration, etc. For example, in certain embodiments, administration to an animal subject (e.g., to a human or a rodent) may be bronchial (including by bronchial instillation), buccal, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal and/or vitreal. In some embodiments, administration may involve intermittent dosing. In some embodiments, administration may involve continuous dosing ( e.g., perfusion) for at least a selected period of time. [00169] In some embodiments, determining the absence or presence of activated human T cells in the genetically modified rodent comprises determining the phenotype of human T cells in a sample isolated from the genetically modified rodent, wherein the sample is selected from the group consisting of blood, spleen, and small intestine. In some embodiments, determining the absence or presence of activated human T cells comprises evaluating the activation state of a human T cell isolated from a sample isolated from the genetically modified rodent. In some embodiments, evaluating the activation state of the human T cell comprises determining the expression level of a T cell AIM. In some embodiments, the AIM is selected from the group consisting of Ki67, IFNG, GZMB, 4-1BB, HLA-DR, ICOS, PD1, CD39, CCL5, and any combination thereof. [00170] Also provided herein are methods of identifying a therapeutic candidate for the treatment of a disorder associated with a pathogenic MHC-peptide-TCR interaction. In some embodiments, the method comprises introducing an antigen into a genetically modified rodent as described herein to activate the human T cell into a human effector T cell, administering the therapeutic candidate to the genetically modified rodent, and determining whether the therapeutic candidate reduces, prevents, or inhibits activation of the human T cell into a human effector T cell. In some embodiments, a reduction, prevention, or inhibition of activation of the human T cell into a human effector T cell identifies the therapeutic candidate as capable of treating, e.g., reducing, preventing, or inhibiting, the disorder associated with the pathogenic MHC-peptide- TCR interaction. In some embodiments, introducing the antigen and administering the therapeutic candidate occurs simultaneously. In some embodiments, administering the therapeutic candidate occurs after introducing the antigen. In some embodiments, administering the therapeutic candidate occurs before introducing the antigen. [00171] In some embodiments, the therapeutic candidate comprises a protein that specifically binds to the antigen presented in the context of the antigen presenting portion of the human or humanized MHC, e.g., classical HLA, molecule. In some embodiments, the therapeutic candidate comprises a protein that specifically binds to the recombinant human TCR variable domain. In some embodiments, the therapeutic candidate comprises a protein that specifically binds to both the antigen presented in the context of the antigen presenting portion of the human or humanized MHC, e.g., classical HLA, molecule and the recombinant human TCR variable domain. In some embodiments, the protein comprises an antigen binding protein (e.g., an antibody) or a binding fragment thereof. In some embodiments, the therapeutic candidate binds gliadin, or a portion, thereof presented in the context of HLA-DQ2.5. In some embodiments, the therapeutic candidate binds the recombinant human TCR variable domain that binds gliadin, or a portion thereof, presented in the context of the antigen presenting portion of HLA-DQ2.5. In some embodiments, the therapeutic candidate binds gliadin, or a portion thereof presented in the context of HLA-DQ2.5 and the recombinant human TCR variable domain that binds gliadin, or a portion thereof, presented in the context of the antigen presenting portion of HLA-DQ2.5. EXAMPLES [00172] The invention will be further illustrated by the following nonlimiting examples. These Examples are set forth to aid in the understanding of the invention but are not intended to, and should not be construed to, limit its scope in any way. The Examples do not include detailed descriptions of conventional methods that would be well known to those of ordinary skill in the art (molecular cloning techniques, etc.). Unless indicated otherwise, parts are parts by weight, molecular weight is average molecular weight, temperature is indicated in Celsius, and pressure is at or near atmospheric. Example 1. Generation of Genetically Modified HLA-DQ2.5 Mice [00173] Mice genetically modified to express chimeric human HLA-DQ2.5/H-2A protein were made using VELOCIGENE® genetic engineering technology (see, e.g., US Pat. No. 6,586,251 and Valenzuela et al., 2003, High-throughput engineering of the mouse genome coupled with high-resolution expression analysis, Nature Biotech. 21(6):652-659). LTVECs harboring humanized genes were generated by gene synthesis and modification of BACs by bacterial homologous recombination and digestion/ligation techniques. Methods of making mice genetically modified to express chimeric human/rodent MHC are described in U.S. Patent Nos. 9,615,550; 10,869,466; 9,591,835; 10,045,516; and 10,779,520, each of which is incorporated by reference herein in its entirety. [00174] Human HLA-DQ2.5 α and β chain sequences were synthesized by Blue Heron Gene Synthesis Company (WA, USA) based on publicly available gene sequences. Specifically, synthesized human HLA-DQ2.5 α (DQA1*05) and β (DQB1*02) chains and mouse BAC RP23- 444J20 were modified and used to generate an LTVEC comprising chimeric HLA-DQ2.5/H-2A genes, depicted in Figure 1. The nucleotide sequence junctions of the resulting LTVEC (e.g., mouse/human sequence junctions, human/mouse sequence junctions, or junctions of mouse or human sequence with selection cassettes) are summarized below in Table 2 and listed in the Sequence Listing; their locations are indicated in the schematic diagram of Figure 1. In Table 2 below, the mouse sequences are in regular font; the human sequences are in parentheses; the Lox sequences are italicized; and the restriction sites introduced during cloning steps and other vector-based sequences (e.g., multiple cloning sites, etc.) are bolded.
Table 2: Junctions of LTVEC for HLA-DQ2.5/H-2A Mice SEQ Nucleotide Sequence ID C ) ) [00175] The large targeting vector was used to electroporate MAID5111 ES cells (ES cells which comprise a deletion of the entire MHC locus) to create modified ES cells comprising a replacement of the endogenous mouse I-A and I-E loci with a genomic fragment comprising a chimeric HLA-DQ2.5/H-2A (Figure 1). Positive ES cells containing deleted endogenous I-A and I-E loci replaced by the genomic fragment comprising the chimeric locus were identified by a quantitative PCR assay using TAQMAN™ probes (Lie and Petropoulos (1998) Curr. Opin. Biotechnology 9:43-48). [00176] Positive ES cell clones were then used to implant female mice using the VELOCIMOUSE® method (see, e.g., US Pat. No. 7,294,754 and Poueymirou et al. (2007) Nature Biotech. 25(1):91-99) to generate a litter of pups containing a replacement of the endogenous I-A and I-E loci with the chimeric human/mouse locus. Targeted ES cells are used as donor ES cells and introduced into an 8-cell stage mouse embryo by the VELOCIMOUSE® method. Mice bearing the chimeric human/mouse locus were identified by genotyping using a modification of allele assay (Valenzuela et al., supra) that detects the presence of a chimeric human/mouse locus. [00177] Mice bearing the chimeric human/mouse locus were bred to a Cre deletor mouse strain (see, e.g., International Patent Application Publication No. WO 2009/114400) in order to remove any loxed neomycin or hygromycin cassette introduced by the targeting vector that is not removed, e.g., at the ES cell stage or in the embryo. [00178] Mice homozygous for the individual genetic modifications, e.g., humanizations, (e.g., HLA-DQ2.5/H-2A, IL15h/h, SIRPAh/h, etc.) and/or null mutations (e.g., Rag2-/-, Il2rg-/-, etc.) (see, e.g., U.S. Patent Nos.9,615,550; 10,869,466; 9,591,835; 10,045,516; 10,779,520; and 9,193,977 and PCT Patent Application Publication No. WO 2016/168212, incorporated herein by reference) are bred together using methods known in the art to obtain a mouse comprising all desired genetic modifications (e.g., HLA-DQ2.5/H-2A, IL15h/h, SIRPAh/h, Rag2-/-, Il2rg-/-, etc.). Mice are bred to homozygosity using methods known in the art. Alternatively, targeting vectors comprising each desired humanized gene and/or null mutation genes are introduced via sequential targeting into the same ES cell to obtain an ES cell comprising all genetic modifications (e.g., humanized HLA-DQ2.5/H-2A, human IL15 and SIRPA, and lacking functional endogenous Rag2 and Il2rg, etc.) and the resultant ES cell is introduced into 8-cell stage mouse embryo by the VELOCIMOUSE® method. Example 2. Generation and Characterization of Gliadin-specific T cells [00179] As depicted in Figure 2A, CRISPR/CAS9 was used to knock-out the endogenous T-cell receptor (TCR), and lentiviral transduction was used to introduce an HLA-DQ2.5- restricted TCR against α1-gliadin, in human T-cells. Figure 2B depicts flowplots of human T cells gated for CD3 and TCRαβ expression, demonstrating a significant decrease in double positive cells following CRISPR/CAS9-mediated deletion of the endogenous T cell receptor (middle flowplot) as compared to wild-type (WT) T cells (left flowplot) and restoration of double positive cells following lentiviral transduction with the HLA-DQ2.5-restricted ⍺1- gliadin-specific TCR (right flowplot) to levels comparable to WT. Accordingly, it is shown that the genetically modified T cells express a fully assembled engineered TCR:CD3 complex. Figure 2C depicts a quantification of IFNγ production in TCR knockout (gray) and engineered (black) CD4 (left panel) and CD8 (right panel) T cells stimulated with vehicle, 10µM of α1- gliadin peptide, 10µM of α2-gliadin peptide, or PMA + Ionomycin as a positive control. Notably, IFNγ is produced in CD4 and CD8 T cells comprising the HLA-DQ2.5-restricted TCR in response to simulation with α1-gliadin peptide but not α2-gliadin peptide, confirming that the engineered T cells are specific for α1-gliadin. Materials and Methods CRISPR-Cas9 mediated knockout of TRAC and TRBC [00180] Untouched T cells were enriched from healthy donor PBMC using EasySep Human T Cell Isolation Kit (#17951, Stem Cell Technologies) and incubated with 1:1 Dynabeads™ Human T-Activator CD3/CD28 for T Cell Expansion and Activation (11131D, Thermo Fisher Scientific) and 30U/mL of IL-2 (130-097-745, Miltenyi Biotech) in CTS OpTimizer T cell expansion media (A1048501, Gibco) for 72h. Next, beads were removed, and T cells were resuspended in P3 Primary Cell 4D-Nucleofector (Lonza) containing 180pmol of gRNA and 90pmol of TrueCut Cas9 protein v2 (A36496, Thermo) of gRNA A and gRNA B (gRNA targeting TCR alpha constant domain (TRAC) and TCR beta constant domain (TRAB), respectively) (see Figure 2A, Step 1), and transferred into cuvette. RNPs were electroporated using DS-137 pulse using Amaxa 4D-nucleofector (Lonza). Immediately after pulse, 1e6 cells were transferred on 24-well plates and proceeded with viral transduction. Lentiviral Vector [00181] Genes encoding the TCR of interest were assembled and cloned under the Spleen Focus-Forming Virus (SFFV) or Elongation factor 1-alpha 1 (EF1a) promoter into a 3rd generation mammalian gene expression lentiviral vector pLV (VectorBuilder) and packaged into VSV-G pseudotyped third-generation lentivirus (VectorBuilder). Viral transduction of recombinant TCR [00182] For lentiviral transduction, previously electroporated cells were incubated with respective viral construct (see Figure 2A, Step 2) at MOI=5 in a presence of 1:1 Dynabeads™ Human T-Activator CD3/CD28 for T Cell Expansion and Activation (11131D, Thermo Fisher Scientific), 100U/mL of IL-2 (130-097-745, Miltenyi Biotech) and 2mg/ml of Lentiboost-P (Sirion Biotech) in CTS OpTimizer T cell expansion media (A1048501, Gibco). Next, plate was centrifuged at 1200g, 32C for 90mins. In vitro expansion of engineered TCR T cells [00183] T cell cultures were expanded with Human T-activator CD3/CD28 dynabeads (life technologies) in 1:1 ratio with the presence of 100U/ml of recombinant human IL-2 (human IL-2 IS, Miltenyi Biotec) and 0.5ng/ml of recombinant human IL-15 (Peprotech). Fresh OpTmizer media (CTS OpTmizer T Cell Expansion SFM, Life Technologies) were replenished every 2-3 days in the presence of both IL-2 and IL-15 cytokines. Cell culture was kept at 0.5 to 1e6 cells/ml concentration and expanded for up to 20 days in vitro. Cells were then frozen down for future use. In vitro stimulation assay of engineered TCR T cells for IFNγ production [00184] 105 in vitro expanded Gliadin-α1 TCR T cells, both CD4+ and CD8+, were co- cultured with 3 x 105 of RAJI in a 96 well U-bottom plate with OpTmizer T cell expansion media (CTS OpTmizer T Cell Expansion SFM, Life Technologies). Cells were stimulated separately with vehicle, 10µM of α1 peptide, 10µM of α2 peptide, and PMA Ionomycin cocktail (Cell activation cocktail, Biolegend) as a positive control. Co-stimulator antibody anti-CD28 was added at a final concentration of 0.25µg/ml. The culture was incubated in the 37oC, 5% CO2 incubator for 4 hours. Brefeldin A (5µg/ml, Biolegend) solution was added to the culture after 1 hour of incubation. After incubation, the cells were stained immediately. The cells were washed once with 1x DPBS (Life Technologies) and stained with Live/Dead solution (Life technologies) for 15 minutes at room temperature in the dark. Cells were stained for cell surface markers for 30 minutes at 4oC in the dark. Cells were then washed twice and fixed (Cyto-Fast Fix/Perm Buffer set, Biolegend) for 20 minutes at room temperature in the dark. Cells were then washed twice with 1x perm buffer and either leave in perm buffer or stained with intracellular antibody cocktail mix for 20 minutes at room temperature in the dark. Cells were then washed twice with 1x perm buffer and resuspended with MACS buffer ( Miltenyi Biotec) and acquired samples with BD symphony flow cytometry. Example 3. Mouse model expressing HLA-DQ2.5/H-2A and comprising T cells expressing HLA-DQ2.5-restricted ⍺1-gliadin-specific TCR [00185] Gluten-specific T-cells are drivers of celiac disease (CeD), and 90-95% of CeD patients carry the HLA-DQ2.5 encoding alleles. In the present Example, a mouse model of gluten-specific human T-cell activation was generated using engineered T cells adoptively transferred into HLA-DQ2.5-expressing mice exposed to gliadin. [00186] The engineered CD4+ and CD8+ T-cells of Example 2 were transferred into humanized HLA-DQ2.5 mice that also comprised human IL15 and SIRPA, on a Rag2-/-/Il2rg-/- background (see Example 1). Humanized HLA-DQ2.5/H-2A-expressing mice were administered by oral gavage either a vehicle control or a gliadin peptide 3 times per week for 2 weeks, and blood, spleen and small intestine were analyzed by flow cytometry and real-time qPCR. [00187] In blood, spleen and small intestine tissue of humanized HLA-DQ2.5-knock-in mice, oral gavage with gliadin induced proliferation (Ki67+) of gliadin-specific human CD4+ T- cells, which exhibited an increased percentage of cells with an effector memory phenotype (Figures 3A-3C; left and right panels). In addition, the transferred human T-cells presented with an activated phenotype, with increased expression of OX40 in the spleen, as well as granzyme B and CD69 in the small intestine (data not shown). Moreover, granzyme B expression was significantly elevated in engineered CD4+ T cells from the blood and spleen of gliadin-treated mice (Figures 3A-3C; middle panels). In addition, in mice that received the oral gavage with gliadin, engineered CD8+ T-cells exhibited an increase in Ki67 and GzmB expression in the blood, spleen, and small intestine; while an increased proportion of CD8+ T-cells presented a central memory phenotype when compared to the engineered cells in control mice (Figures 4A- 4C). Analysis of mRNA expression of human genes revealed an increase in IFNγ, Granzyme B (GzmB) and CCL5 in the small intestine of mice that were exposed to gliadin (Figure 5A). Cytokine measurement in the serum revealed an increase in IFNγ, IL-2 and TNF-α in mice that were fed with gliadin compared to mice receiving the vehicle control (Figure 5B). Moreover, similar effects were observed using additional T cells that were engineered to express other HLA-DQ2.5-restricted TCRs against α gliadin, e.g., comprising TCR α and β variable domains specific for gliadin (data not shown). [00188] Herein it is demonstrated that gliadin-specific human T-cells exhibit an activated phenotype in HLA-DQ2.5-expressing mice upon oral gavage with gliadin. Without being bound by theory, this model may be useful for studying the immunogenic potential of gluten-containing food and for evaluating therapeutics targeting gliadin antigen presentation or gliadin-specific human T-cells in vivo. Materials and Methods Mouse study and Flow Cytometry Analysis [00189] Mice that were knocked-in for HLA-DQ2.5/H-2A, human IL15 and SIRPA, on a Rag2-/-/Il2rg-/- background, were maintained on a gluten-free diet (AIN76) throughout the experiment. Mice were transferred with 6 x 106 engineered TCR T cells and the mice were treated via oral gavage 3 times per week with vehicle PBS or 5mg of a synthetic α1/α2 gliadin- derived peptide of the following amino acid sequence QLQPFPQPELPYPQPQ (SEQ ID NO: 7). 14 days after adoptive transfer, the mice were euthanized, and tissues were processed for single cell suspension and analyzed by flow cytometry. TaqMan PCR analysis of gene expression [00190] Tissue samples were placed in tubes containing 400 μl of RNAlater and stored at −20°C. All samples were homogenized in TRIzol, and chloroform was used for phase separation. The aqueous phase, containing total RNA, was purified using MagMAX-96 for the Microarrays Total RNA Isolation Kit (Ambion by Life Technologies) according to the manufacturer’s specifications. Genomic DNA was removed using RNase-Free DNase Set (QIAGEN). mRNA was reverse-transcribed into cDNA using the SuperScript VILO Master Mix (Invitrogen by Life Technologies). cDNA was diluted to 2 ng/μl, and 10 ng of cDNA were amplified with the SensiFAST Probe Hi-ROX (Meridian) using the ABI 7900HT Sequence Detection System (Applied Biosystems). ACTB (β-actin) was used as the internal control gene to normalize any cDNA input differences. Data were reported as expression relative to the control gene. Cytokine measurement in the serum [00191] Cytokine concentrations in the serum were measured using Meso Scale Discovery (MSD) V-PLEX Proinflammatory Panel 1 human immunoassay kits (Rockville, MD) according to the manufacturer’s instructions. Electrochemiluminescence was read on an MSD Spector instrument and quantification of samples were achieved with the MSD discovery workbench analysis software. EQUIVALENTS [00192] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents of the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims. [00193] The entire contents of all non-patent documents, patent applications and patents cited throughout this application are incorporated by reference herein in their entirety.

Claims

CLAIMS What is claimed: 1. A genetically modified rodent model comprising: (a) in its genome, a first recombinant nucleic acid, wherein the first recombinant nucleic acid encodes at least an antigen presenting portion of a classical human leukocyte antigen (HLA) molecule, wherein the antigen presenting portion of the classical HLA molecule comprises α1, α2, and α3 domains of a classical HLA class I molecule; or α1, α2, β1, and β2 domains of a classical HLA class II molecule; and (b) in its periphery, a human T cell, wherein the human T cell is genetically modified to express a second recombinant nucleic acid that encodes a recombinant human T cell receptor (TCR) variable domain, wherein the human T cell expresses the recombinant human TCR variable domain on its cell surface, and wherein the recombinant human TCR variable domain binds an antigen presented in the context of the antigen presenting portion of the classical HLA molecule.
2. The genetically modified rodent model of claim 1, wherein: the first recombinant nucleic acid is at an endogenous classical MHC locus, and/or the first recombinant nucleic acid replaces an endogenous classical MHC gene or portion thereof, and/or the genetically modified rodent is homozygous for a replacement of the endogenous classical MHC gene or portion thereof with the first recombinant nucleic acid.
3. The genetically modified rodent model of claim 1 or claim 2, wherein the second recombinant nucleic acid is operably linked to a non-human promoter that controls expression of the recombinant human TCR variable domain and/or wherein the second recombinant nucleic acid is operably linked to a non-human regulatory element that enhances expression of the recombinant human TCR variable domain.
4. The genetically modified rodent model of claim 3, wherein the non-human promoter is an EF1α promoter, or a spleen focus-forming virus (SFFV) promoter.
5. The genetically modified rodent model of claim 3 or claim 4, wherein the non-human regulatory element is Woodchuck posttranscriptional regulatory element (WPRE).
6. The genetically modified rodent model of any one of claims 1-5, wherein the second recombinant nucleic acid is episomal, randomly integrated, or replaces an endogenous TCR sequence at an endogenous TCR locus.
7. The genetically modified rodent model of any one of claims 1-6, wherein the recombinant human TCR variable domain is expressed fused to a linker sequence.
8. The genetically modified rodent model of claim 7, wherein the linker sequence comprises a furin-cleavable linker.
9. The genetically modified rodent model of any one of claims 1-8, wherein the human T cell comprises a viral nucleic acid.
10. The genetically modified rodent model of claim 9, wherein the viral nucleic acid comprises a viral nucleic acid encoding a 2A peptide.
11. The genetically modified rodent model of claim 10, wherein the 2A peptide is selected from the group consisting of: a T2A peptide, a P2A peptide, and a F2A peptide.
12. The genetically modified rodent model of claim 9, wherein the viral nucleic acid comprises an adeno-associated viral (AAV) nucleic acid.
13. The genetically modified rodent model of claim 12, wherein the AAV nucleic acid comprises an AAV inverted terminal repeat (ITR).
14. The genetically modified rodent model of any one of claims 1-13, wherein the genetically modified rodent does not comprise, in its periphery: (i) mature rodent B cells, (ii) mature rodent T cells, and/or (iii) rodent NK cells.
15. The genetically modified rodent model of any one of claims 1-14, wherein the genetically modified rodent further comprises, in its genome: (i) a knockout mutation of an endogenous Rag gene, and/or (ii) a knockout mutation of an endogenous interleukin-2 receptor (Il2r) gene.
16. The genetically modified rodent model of claim 15, wherein the endogenous Rag gene comprises an endogenous Rag2 gene.
17. The genetically modified rodent model of claim 15 or claim 16, wherein the genetically modified rodent is homozygous for the knockout mutation of the endogenous Rag gene.
18. The genetically modified rodent model of any one of claims 15-17, wherein the endogenous Il2r gene comprises an endogenous Il2rγ gene.
19. The genetically modified rodent model of any one of claims 15-18, wherein the genetically modified rodent is homozygous for the knockout mutation of the endogenous Il2r gene.
20. The genetically modified rodent model of any one of claims 1-19, wherein the genetically modified rodent further comprises, in its genome: (i) a human or humanized interleukin-15 (IL15) gene, and/or (ii) a human or humanized Signal Regulatory Protein Alpha (SIRPA) gene.
21. The genetically modified rodent model of claim 20, wherein the human or humanized IL15 gene is at an endogenous Il15 locus and/or replaces an endogenous Il15 gene.
22. The genetically modified rodent model of claim 20 or claim 21, wherein the genetically modified rodent is homozygous for a replacement of the endogenous Il15 gene with the human or humanized IL15 gene.
23. The genetically modified rodent model of any one of claims 20-22, herein the human or humanized SIRPA gene is at an endogenous sirpa locus and/or replaces an endogenous sirpa gene.
24. The genetically modified rodent model of any one of claims 20-23, wherein the genetically modified rodent is homozygous for a replacement of the endogenous sirpa gene with the human or humanized SIRPA gene.
25. The genetically modified rodent model of any one of claims 1-24, wherein the human T cell is an activated effector T cell.
26. The genetically modified rodent model of any one of claims 1-25, wherein the genetically modified rodent exhibits one or more symptoms of a disease associated with the classical HLA molecule, the antigen or the combination of the classical HLA molecule and the antigen.
27. The genetically modified rodent model of any one of claims 1-26, wherein the first recombinant nucleic acid encodes at least an antigen presenting portion of an HLA-B molecule, an HLA-DR1 molecule, an HLA-DR2 molecule, an HLA-DR3 molecule, an HLA-DR4 molecule, an HLA-DR13 molecule, an HLA-DR15 molecule, an HLA-DQ2 molecule, an HLA- DQ4 molecule, an HLA-DQ8 molecule, an HLA-DQ9 molecule, or a combination thereof.
28. The genetically modified rodent model of any one of claims 1-27, wherein the first recombinant nucleic acid encodes at least an antigen presenting portion of an HLA molecule that is associated with a disease as set forth in Table 1, wherein the antigen comprises an antigen, or a portion thereof, that is associated with the disease as set forth in Table 1, and wherein the genetically modified rodent exhibits one or more characteristics of the disease.
29. The genetically modified rodent model of any one of claims 1-28, wherein the first recombinant nucleic acid encodes at least an antigen presenting portion of an HLA-DQ2.5 molecule, wherein the antigen is gliadin, or a portion thereof, and wherein the genetically modified rodent model exhibits one or more characteristics of celiac disease.
30. The genetically modified rodent model of any one of claims 1-29, wherein the genetically modified rodent comprises an activated effector T cell that specifically binds gliadin, or the portion thereof, presented in the context of the antigen presenting portion of HLA-DQ2.5.
31. The genetically modified rodent model of claim 25 or claim 30, wherein the activated effector T cell expresses an activation-induced marker (AIM).
32. The genetically modified rodent model of claim 31, wherein the AIM is selected from the group consisting of Ki67, IFNG, GZMB, 4-1BB, HLA-DR, ICOS, PD1, CD39, and CCL5.
33. The genetically modified rodent model of any one of claims 25, and 30-32, wherein the activated effector T cell is found in the blood, spleen and/or small intestine of the genetically modified rodent.
34. The genetically modified rodent model of any one of claims 1-33, wherein the genetically modified rodent is a genetically modified mouse.
35. The genetically modified rodent model of claim 34, wherein the genetically modified mouse comprises: (a) in its genome, (i) the first recombinant nucleic acid, wherein the first recombinant nucleic acid encodes at least the α1, α2, β1, and β2 domains of a classical HLA-DQ2.5 class II molecule, (ii) a human or humanized SIRPA gene, (iii) a homozygous knockout mutation of an endogenous Rag2 gene, and (iv) a homozygous knockout mutation of an endogenous Il2rγ gene; and (b) in its periphery, the human T cell, wherein the human T cell expresses the recombinant human TCR variable domain on its cell surface, wherein the recombinant human TCR variable domain recognizes gliadin presented in the context of the α1, α2, β1, and β2 domains of the classical HLA-DQ2.5 class II molecule.
36. The genetically modified rodent model of claim 34 or claim 35, wherein the genetically modified mouse comprises: (a) in its genome, (i) the first recombinant nucleic acid, wherein the first recombinant nucleic acid encodes at least the α1, α2, β1, and β2 domains of a classical HLA-DQ2.5 class II molecule, (ii) a human or humanized IL15 gene, (iii) a human or humanized SIRPA gene, (iv) a homozygous knockout mutation of an endogenous Rag2 gene, and (v) a homozygous knockout mutation of an endogenous Il2rγ gene; and (b) in its periphery, the human T cell, wherein the human T cell expresses the recombinant human TCR variable domain on its cell surface, wherein the recombinant human TCR variable domain recognizes gliadin presented in the context of the α1, α2, β1, and β2 domains of the classical HLA-DQ2.5 class II molecule.
37. The genetically modified rodent model of any one of claims 1-36, wherein the recombinant human TCR variable domain comprises: (i) a TCR α variable domain encoded by a TRAV9-2 gene segment and comprising a complementary determining region (CDR) 3 that comprises an amino acid sequence of ALSDHYSSGSARQLT (SEQ ID NO: 10), and (ii) a TCR β variable domain encoded by a TRBV7-2 gene segment and comprising a CDR3 that comprises an amino acid sequence of ASSTAVLAGGPQY (SEQ ID NO: 14).
38. The genetically modified rodent model of any one of claims 1-37, wherein the recombinant human TCR variable domain comprises: (i) a TCR α variable domain encoded by a TRAV9-2 gene segment and comprising a an amino acid sequence as set forth in SEQ ID NO: 11, and (ii) a TCR β variable domain encoded by a TRBV7-2 gene segment and comprising an amino acid sequence as set forth in SEQ ID NO: 15.
39. The genetically modified rodent model of any one of claims 1-38, wherein the human T cell: (a) exhibits an effector memory phenotype, (b) is found in the blood, spleen, or small intestine, and/or (c) expresses an AIM.
40. The genetically modified rodent model of claim 39, wherein the effector memory phenotype comprises an expression pattern selected from the group consisting of: CD45RO+, CD62L-, CCR7lo, and CD45RA-.
41. The genetically modified rodent model of claim 39 or claim 40, wherein the AIM is selected from the group consisting of: Ki67, IFNG, GZMB, 4-1BB, HLA-DR, ICOS, PD1, CD39, and CCL5.
42. The genetically modified rodent model of any one of claims 1-41, wherein the genetically modified rodent further comprises an antigen that binds to the antigen presenting portion of the classical HLA molecule.
43. The genetically modified rodent model of claim 42, wherein the recombinant human TCR variable domain binds the antigen presented in the context of the antigen presenting portion of the classical HLA molecule.
44. The genetically modified rodent model of claim 42 or claim 43, wherein the antigen is a gliadin peptide.
45. A method of making a genetically modified rodent model of disease, the method comprising administering the antigen to the genetically modified rodent model of any one of claims 1-41.
46. The method of claim 45, further comprising: determining, after administering the antigen, the absence or presence of activated human T cells in the genetically modified rodent, wherein the presence of activated human T cells in the genetically modified rodent indicates that the genetically modified rodent is modeling the disease.
47. The method of claim 45 or claim 46, wherein the genetically modified rodent is a genetically modified mouse, wherein the genetically modified mouse comprises: (a) in its genome, (i) the first recombinant nucleic acid, wherein the first recombinant nucleic acid encodes at least the α1, α2, β1, and β2 domains of a classical HLA-DQ2.5 class II molecule, (ii) a human or humanized SIRPA gene, (iii) a homozygous knockout mutation of an endogenous Rag2 gene, and (iv) a homozygous knockout mutation of an endogenous Il2rγ gene; and (b) in its periphery, the human T cell, wherein the human T cell expresses the recombinant human TCR variable domain on its cell surface, wherein the recombinant human TCR variable domain recognizes gliadin presented in the context of the α1, α2, β1, and β2 domains of the classical HLA-DQ2.5 class II molecule.
48. The method of any one of claims 45-47, wherein the genetically modified rodent is a genetically modified mouse, wherein the genetically modified mouse comprises: (a) in its genome, (i) the first recombinant nucleic acid, wherein the first recombinant nucleic acid encodes at least the α1, α2, β1, and β2 domains of a classical HLA-DQ2.5 class II molecule, (ii) a human or humanized IL15 gene, (iii) a human or humanized SIRPA gene, (iv) a homozygous knockout mutation of an endogenous Rag2 gene, and (v) a homozygous knockout mutation of an endogenous Il2rγ gene; and (b) in its periphery, the human T cell, wherein the human T cell expresses the recombinant human TCR variable domain on its cell surface, wherein the recombinant human TCR variable domain recognizes gliadin presented in the context of the α1, α2, β1, and β2 domains of the classical HLA-DQ2.5 class II molecule.
49. The method of any one of claims 45-48, wherein administering comprises oral gavage with a gliadin peptide.
50. The method of any one of claims 45-49, wherein determining the absence or presence of activated human T cells in the genetically modified rodent comprises determining the phenotype of human T cells in a sample isolated from the genetically modified rodent, wherein the sample is selected from the group consisting of blood, spleen, and small intestine.
51. The method of any one of claims 45-50, wherein determining the absence or presence of activated human T cells comprises evaluating the activation state of a human T cell isolated from a sample isolated from the genetically modified rodent.
52. The method of claim 51, wherein evaluating the activation state of the human T cell comprises determining the expression level of a T cell AIM.
53. The method of claim 52, wherein the AIM is selected from the group consisting of Ki67, IFNG, GZMB, 4-1BB, HLA-DR, ICOS, PD1, CD39, CCL5, and any combination thereof.
54. A method of identifying a therapeutic candidate for the treatment of a disorder associated with a pathogenic MHC-peptide-TCR interaction, the method comprising: introducing, into the genetically modified rodent model of any one of claims 1-41, an antigen that binds the recombinant human TCR variable domain when presented in the context of the antigen presenting portion of the classical HLA molecule, wherein the antigen bound to the antigen presenting portion of the classical HLA molecule activates the human T cell into a human effector T cell, administering the therapeutic candidate to the genetically modified rodent, and determining whether the therapeutic candidate reduces, prevents, or inhibits activation of the human T cell into a human effector T cell, wherein a reduction, prevention, or inhibition of activation of the human T cell into a human effector T cell identifies the therapeutic candidate as capable of treating the disorder associated with the pathogenic MHC-peptide-TCR interaction.
55. The method of claim 54, wherein introducing the antigen and administering the therapeutic candidate occurs simultaneously.
56. The method of claim 54, wherein administering the therapeutic candidate occurs after introducing the antigen.
57. The method of claim 54, wherein administering the therapeutic candidate occurs before introducing the antigen.
58. The method of any one of claims 54-57, wherein the therapeutic candidate comprises a protein that specifically binds to (i) the antigen presented in the context of the antigen presenting portion of the classical HLA molecule, (ii) the recombinant human TCR variable domain, or (iii) both the antigen presented in the context of the antigen presenting portion of the classical HLA molecule and the recombinant human TCR variable domain.
59. The method of claim 58, wherein the protein comprises an antigen-binding protein or a binding fragment thereof.
60. The method of claim 58 or claim 59, wherein the protein comprises an antibody or an antigen-binding portion thereof.
61. The method of any one of claims 54-60, wherein the genetically modified rodent is a genetically modified mouse, wherein the genetically modified mouse comprises: (a) in its genome, (i) the first recombinant nucleic acid, wherein the first recombinant nucleic acid encodes at least the α1, α2, β1, and β2 domains of a classical HLA-DQ2.5 class II molecule, (ii) a human or humanized SIRPA gene, (iii) a homozygous knockout mutation of an endogenous Rag2 gene, and (iv) a homozygous knockout mutation of an endogenous Il2rγ gene; and (b) in its periphery, the human T cell, wherein the human T cell expresses the recombinant human TCR variable domain on its cell surface, wherein the recombinant human TCR variable domain recognizes gliadin presented in the context of the α1, α2, β1, and β2 domains of the classical HLA-DQ2.5 class II molecule.
62. The method of any one of claims 54-61, wherein the genetically modified rodent is a genetically modified mouse, wherein the genetically modified mouse comprises: (a) in its genome, (i) the first recombinant nucleic acid, wherein the first recombinant nucleic acid encodes at least the α1, α2, β1, and β2 domains of a classical HLA-DQ2.5 class II molecule, (ii) a human or humanized IL15 gene, (iii) a human or humanized SIRPA gene, (iv) a homozygous knockout mutation of an endogenous Rag2 gene, and (v) a homozygous knockout mutation of an endogenous Il2rγ gene; and (b) in its periphery, the human T cell, wherein the human T cell expresses the recombinant human TCR variable domain on its cell surface, wherein the recombinant human TCR variable domain recognizes gliadin presented in the context of the α1, α2, β1, and β2 domains of the classical HLA-DQ2.5 class II molecule.
63. The method of claim 61 or claim 62, wherein the therapeutic candidate binds (i) gliadin, or a portion thereof, presented in the context of HLA-DQ2.5 and/or (ii) the recombinant human TCR variable domain that binds gliadin, or a portion thereof, presented in the context of the antigen presenting portion of HLA-DQ2.5.
64. A method of making the genetically modified rodent model of any one of claims 1-41, wherein the method comprises: introducing, into a genetically modified rodent, a genetically modified human T cell, wherein the genetically modified human T cell expresses a recombinant human TCR variable domain that binds an antigen presented in the context of an antigen presenting portion of a classical HLA molecule, and wherein the genetically modified rodent expresses at least the antigen presenting portion of the classical HLA molecule.
65. The method of claim 64, wherein the genetically modified rodent comprises, in its genome, a recombinant nucleic acid that encodes the antigen presenting portion of the classical HLA molecule.
66. The method of claim 65, wherein the antigen presenting portion of the classical HLA molecule comprises α1, α2, and α3 domains of a classical HLA class I molecule; or α1, α2, β1, and β2 domains of a classical HLA class II molecule.
67. The method of claim 66, wherein: the recombinant nucleic acid that encodes the antigen presenting portion of the classical HLA molecule is at an endogenous classical MHC locus; and/or the recombinant nucleic acid that encodes the antigen presenting portion of the classical HLA molecule replaces an endogenous classical MHC gene or portion thereof; and/or the genetically modified rodent is homozygous for a replacement of an endogenous classical MHC gene or portion thereof with the recombinant nucleic acid.
68. The method of any one of claims 64-67, wherein the genetically modified human T cell is introduced into the genetically modified rodent by intravenous injection.
69. The method of any one of claims 64-68, wherein a recombinant nucleic acid that encodes the recombinant human TCR variable domain that binds the antigen presented in the context of an antigen presenting portion of the classical HLA molecule: is operably linked to a non-human promoter that controls expression of the recombinant human TCR variable domain and/or a non-human regulatory element that enhances expression of the recombinant human TCR variable domain; comprises a non-human nucleic acid, and/or is episomal, randomly integrated, or replaces an endogenous TCR sequence at an endogenous TCR locus.
70. The method of claim 69, wherein the non-human promoter is an EF1α promoter, or an SFFV promoter.
71. The method of claim 69, wherein the non-human regulatory element is WPRE.
72. The method of claim 69, wherein the non-human nucleic acid comprises a viral nucleic acid.
73. The method of claim 72, wherein the viral nucleic acid comprises a viral nucleic acid encoding a 2A peptide.
74. The method of claim 73, wherein the 2A peptide is selected from the group consisting of: a T2A peptide, a P2A peptide, and a F2A peptide.
75. The method of claim 72, wherein the viral nucleic acid comprises an AAV nucleic acid.
76. The method of claim 75, wherein the AAV nucleic acid comprises an AAV ITR.
77. The method of any one of claims 64-76, wherein the recombinant human TCR variable domain is expressed fused to a linker sequence.
78. The method of claim 77, wherein the linker sequence comprises a furin-cleavable linker.
79. The method of any one of claims 64-78, comprising making the genetically modified rodent.
80. The method of claim 79, wherein making the genetically modified rodent comprises modifying the genome of a rodent to comprise the recombinant nucleic acid that encodes the antigen presenting portion of the classical HLA molecule.
81. The method of claim 80, wherein making the genetically modified rodent further comprises modifying the genome of a rodent to comprise one or more knockout mutations that provide for an immunodeficient background and/or one or more humanizations in which an exogenous nucleic acid sequence is inserted into the genome of the rodent to form a humanized gene that encodes a human or humanized polypeptide that promotes the development and/or function of transplanted human cells.
82. The method of claim 81, wherein modifying the genome of the rodent comprises: (a) sequentially modifying an embryonic stem (ES) cell to comprise the recombinant nucleic acid that encodes the antigen presenting portion of the classical HLA molecule, and the one or more knockout mutations that provide for an immunodeficient background and/or the one or more humanizations in which an exogenous nucleic acid sequence is inserted into the genome of the rodent to form a humanized gene that encodes a human or humanized polypeptide that promotes the development and/or function of transplanted human cells; and (b) introducing the ES cell into a rodent host embryo and implanting the rodent host embryo into a surrogate mother for gestation to produce the genetically modified rodent.
PCT/US2025/023109 2024-04-05 2025-04-04 Rodent models of disease Pending WO2025212991A1 (en)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US202463575454P 2024-04-05 2024-04-05
US63/575,454 2024-04-05
US202463641263P 2024-05-01 2024-05-01
US63/641,263 2024-05-01
US202463677856P 2024-07-31 2024-07-31
US63/677,856 2024-07-31

Publications (1)

Publication Number Publication Date
WO2025212991A1 true WO2025212991A1 (en) 2025-10-09

Family

ID=95605544

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2025/023109 Pending WO2025212991A1 (en) 2024-04-05 2025-04-04 Rodent models of disease

Country Status (1)

Country Link
WO (1) WO2025212991A1 (en)

Citations (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6586251B2 (en) 2000-10-31 2003-07-01 Regeneron Pharmaceuticals, Inc. Methods of modifying eukaryotic cells
US7294754B2 (en) 2004-10-19 2007-11-13 Regeneron Pharmaceuticals, Inc. Method for generating an animal homozygous for a genetic modification
WO2009114400A1 (en) 2008-03-07 2009-09-17 Regeneron Pharmaceuticals, Inc. Es cell-derived mice from diploid host embryo injection
WO2013063346A1 (en) 2011-10-28 2013-05-02 Regeneron Pharmaceuticals, Inc. Genetically modified major histocompatibility complex mice
WO2013063340A1 (en) 2011-10-28 2013-05-02 Regeneron Pharmaceuticals, Inc. Transgenic mice expressing chimeric major histocompatibility complex (mhc) class ii molecules
US8541646B2 (en) 2009-10-06 2013-09-24 Regeneron Pharmaceuticals, Inc. Genetically modified mice and engraftment
WO2014039782A2 (en) 2012-09-07 2014-03-13 Yale University Genetically modified non-human animals and methods of use thereof
WO2014071397A2 (en) 2012-11-05 2014-05-08 Regeneron Pharmaceuticals Genetically modified non-human animals and methods of use thereof
US8847004B2 (en) 2011-02-15 2014-09-30 Regeneron Pharmaceuticals, Inc. Humanized M-CSF mice
WO2014164638A1 (en) 2013-03-11 2014-10-09 Regeneron Pharmaceuticals, Inc. Transgenic mice expressing chimeric major histocompatibility comples (mhc) class ii molecules
WO2014164640A1 (en) 2013-03-11 2014-10-09 Regeneron Pharmaceuticals, Inc. Transgenic mice expressing chimeric major histocompatibility complex (mhc) class i molecules
US8878001B2 (en) 2011-10-28 2014-11-04 Regeneron Pharmaceuticals, Inc. Humanized IL-6 and IL-6 receptor
US8962913B2 (en) 2012-06-18 2015-02-24 Regeneron Pharmaceuticals, Inc. Humanized IL-7 rodents
US9043996B2 (en) 2011-10-28 2015-06-02 Regeneron Pharmaceuticals, Inc. Genetically modified major histocompatibility complex animals
US9155290B2 (en) 2013-10-15 2015-10-13 Regeneron Pharmaceuticals, Inc. Humanized IL-15 animals
US9193977B2 (en) 2013-09-23 2015-11-24 Regeneron Pharmaceuticals, Inc. Non-human animals having a humanized signal-regulatory protein gene
US9402377B2 (en) 2010-09-20 2016-08-02 Yale University Human SIRPAalpha transgenic animals and their methods of use
US20160295844A1 (en) * 2015-04-13 2016-10-13 Regeneron Pharmaceuticals, Inc. Genetically modified non-human animals and methods of use thereof
US9591835B2 (en) 2011-10-28 2017-03-14 Regeneron Pharmaceuticals, Inc. Genetically modified major histocompatibility complex animals
US9629347B2 (en) 2013-11-19 2017-04-25 Regeneron Pharmaceuticals, Inc. Non-human animals having a humanized B-cell activating factor gene
US9730435B2 (en) 2013-11-19 2017-08-15 Regeneron Pharmaceuticals, Inc. Non-human animals having a humanized a proliferation-inducing ligand gene
US20220322648A1 (en) * 2021-03-31 2022-10-13 Regeneron Pharmaceuticals, Inc. Genetically modified mice comprising humanized cellular immune system components with improved diversity of tcrb repertoire
US20230172170A1 (en) 2020-04-21 2023-06-08 Regeneron Pharmaceuticals, Inc. Non-human animals having a humanized cxcl13 gene
WO2024020057A1 (en) 2022-07-19 2024-01-25 Regeneron Pharmaceuticals, Inc. Genetically modified animal model and its use to model the human immune system

Patent Citations (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6586251B2 (en) 2000-10-31 2003-07-01 Regeneron Pharmaceuticals, Inc. Methods of modifying eukaryotic cells
US7294754B2 (en) 2004-10-19 2007-11-13 Regeneron Pharmaceuticals, Inc. Method for generating an animal homozygous for a genetic modification
WO2009114400A1 (en) 2008-03-07 2009-09-17 Regeneron Pharmaceuticals, Inc. Es cell-derived mice from diploid host embryo injection
US8541646B2 (en) 2009-10-06 2013-09-24 Regeneron Pharmaceuticals, Inc. Genetically modified mice and engraftment
US9301509B2 (en) 2009-10-06 2016-04-05 Regeneron Pharmaceuticals, Inc. Genetically modified mice and engraftment
US9402377B2 (en) 2010-09-20 2016-08-02 Yale University Human SIRPAalpha transgenic animals and their methods of use
US8847004B2 (en) 2011-02-15 2014-09-30 Regeneron Pharmaceuticals, Inc. Humanized M-CSF mice
US10219493B2 (en) 2011-10-28 2019-03-05 Regeneron Pharmaceuticals, Inc. Genetically modified major histocompatibility complex mice
US9591835B2 (en) 2011-10-28 2017-03-14 Regeneron Pharmaceuticals, Inc. Genetically modified major histocompatibility complex animals
US11219195B2 (en) 2011-10-28 2022-01-11 Regeneron Pharmaceuticals, Inc. Genetically modified major histocompatibility complex mice
US10986822B2 (en) 2011-10-28 2021-04-27 Regeneron Pharmaceuticals, Inc. Genetically modified major histocompatibility complex mice
US10869466B2 (en) 2011-10-28 2020-12-22 Regeneran Pharmaceuticals, Inc. Genetically modified major histocompatibility complex mice
US8878001B2 (en) 2011-10-28 2014-11-04 Regeneron Pharmaceuticals, Inc. Humanized IL-6 and IL-6 receptor
US10779520B2 (en) 2011-10-28 2020-09-22 Regeneron Pharmaceuticals, Inc. Genetically modified major histocompatibility complex animals
US9043996B2 (en) 2011-10-28 2015-06-02 Regeneron Pharmaceuticals, Inc. Genetically modified major histocompatibility complex animals
US20150245598A1 (en) * 2011-10-28 2015-09-03 Regeneron Pharmaceuticals, Inc. Genetically Modified Major Histocompatibility Complex Animals
US9125386B2 (en) 2011-10-28 2015-09-08 Regeneron Pharmaceuticals, Inc. Humanized IL-6 and IL-6 receptor
WO2013063346A1 (en) 2011-10-28 2013-05-02 Regeneron Pharmaceuticals, Inc. Genetically modified major histocompatibility complex mice
US10045516B2 (en) 2011-10-28 2018-08-14 Regeneron Pharmaceuticals, Inc. Genetically modified major histocompatibility complex animals
US9700025B2 (en) 2011-10-28 2017-07-11 Regeneron Pharmaceuticals, Inc. Genetically modified major histocompatibility complex animals
WO2013063340A1 (en) 2011-10-28 2013-05-02 Regeneron Pharmaceuticals, Inc. Transgenic mice expressing chimeric major histocompatibility complex (mhc) class ii molecules
US9615550B2 (en) 2011-10-28 2017-04-11 Regeneron Pharmaceuticals, Inc. Genetically modified major histocompatibility complex mice
US8847005B2 (en) 2011-10-28 2014-09-30 Regeneron Pharmaceuticals, Inc. Genetically modified major histocompatibility complex mice
US9585373B2 (en) 2011-10-28 2017-03-07 Regeneron Pharmaceuticals, Inc. Genetically modified major histocompatibility complex mice
US8962913B2 (en) 2012-06-18 2015-02-24 Regeneron Pharmaceuticals, Inc. Humanized IL-7 rodents
WO2014039782A2 (en) 2012-09-07 2014-03-13 Yale University Genetically modified non-human animals and methods of use thereof
WO2014071397A2 (en) 2012-11-05 2014-05-08 Regeneron Pharmaceuticals Genetically modified non-human animals and methods of use thereof
WO2014164638A1 (en) 2013-03-11 2014-10-09 Regeneron Pharmaceuticals, Inc. Transgenic mice expressing chimeric major histocompatibility comples (mhc) class ii molecules
EP4249507A2 (en) * 2013-03-11 2023-09-27 Regeneron Pharmaceuticals, Inc. Transgenic mice expressing chimeric major histocompatibility complex (mhc) class ii molecules
WO2014164640A1 (en) 2013-03-11 2014-10-09 Regeneron Pharmaceuticals, Inc. Transgenic mice expressing chimeric major histocompatibility complex (mhc) class i molecules
US11019810B2 (en) 2013-09-23 2021-06-01 Regeneron Pharmaceuticals, Inc. Non-human animals having a humanized signal-regulatory protein gene
US9193977B2 (en) 2013-09-23 2015-11-24 Regeneron Pharmaceuticals, Inc. Non-human animals having a humanized signal-regulatory protein gene
US9155290B2 (en) 2013-10-15 2015-10-13 Regeneron Pharmaceuticals, Inc. Humanized IL-15 animals
US9730435B2 (en) 2013-11-19 2017-08-15 Regeneron Pharmaceuticals, Inc. Non-human animals having a humanized a proliferation-inducing ligand gene
US9629347B2 (en) 2013-11-19 2017-04-25 Regeneron Pharmaceuticals, Inc. Non-human animals having a humanized B-cell activating factor gene
WO2016168212A1 (en) 2015-04-13 2016-10-20 Regeneron Pharmaceuticals, Inc. Humanized sirpa-il15 knockin mice and methods of use thereof
US20160295844A1 (en) * 2015-04-13 2016-10-13 Regeneron Pharmaceuticals, Inc. Genetically modified non-human animals and methods of use thereof
US20230172170A1 (en) 2020-04-21 2023-06-08 Regeneron Pharmaceuticals, Inc. Non-human animals having a humanized cxcl13 gene
US20220322648A1 (en) * 2021-03-31 2022-10-13 Regeneron Pharmaceuticals, Inc. Genetically modified mice comprising humanized cellular immune system components with improved diversity of tcrb repertoire
WO2024020057A1 (en) 2022-07-19 2024-01-25 Regeneron Pharmaceuticals, Inc. Genetically modified animal model and its use to model the human immune system

Non-Patent Citations (22)

* Cited by examiner, † Cited by third party
Title
"Genbank", Database accession no. NM_001330728.1
"GenBank", Database accession no. NM_013563.4
"NCBI", Database accession no. XP_005247965.1
AUERBACH ET AL.: "Establishment and Chimera Analysis of 129/SvEv- and C57BL/6-Derived", MOUSE EMBRYONIC STEM CELL LINES, 2000
BARCLAYBROWN, NAT REV IMMUNOL, vol. 6, 2006, pages 457 - 464
DRAKE ET AL., CELL MOL IMMUNOL, vol. 9, no. 3, May 2012 (2012-05-01), pages 215 - 24
FESTING ET AL.: "Revised nomenclature for strain 129 mice", MAMMALIAN GENOME, vol. 10, 1999, pages 836, XP055344303, DOI: 10.1007/s003359901099
FLEUR DU PR� M ET AL: "Tolerance to Ingested Deamidated Gliadin in Mice is Maintained by Splenic, Type 1 Regulatory T Cells", GASTROENTEROLOGY, W.B. SAUNDERS, AMSTERDAM, NL, vol. 141, no. 2, 11 April 2011 (2011-04-11), pages 610 - 620.e2, XP028253746, ISSN: 0016-5085, [retrieved on 20110428], DOI: 10.1053/J.GASTRO.2011.04.048 *
GONNET ET AL.: "Exhaustive Matching of the Entire Protein Sequence Database", SCIENCE, vol. 256, 1992, pages l443 - 45
HOLDSWORTH ET AL.: "The HLA dictionary 2008: a summary of HLA-A, -B, -C, - DRB1/3/4/5, and DQB1 alleles and their association with serologically defined HLA-A, -B, -C, - DR, and -DQ antigens", TISSUE ANTIGENS, vol. 73, 2009, pages 95 - 170
HOLDSWORTH ET AL.: "The HLA dictionary 2008: a summary of HLA-A, -B, -C, -DRB1/3/4/5, and DQB I alleles and their association with serologically defined HLA-A, -B, -C, -DR, and -DQ antigens", TISSUE ANTIGENS, vol. 73, 2009, pages 95 - 170
LIEPETROPOULOS, CURR. OPIN. BIOTECHNOLOGY, vol. 9, 1998, pages 43 - 48
MARSH ET AL.: "Nomenclature for factors of the HLA system", TISSUE ANTIGENS, vol. 75, 2010, pages 291 - 455
POUEYMIROU ET AL., NATURE BIOTECH, vol. 25, no. 1, 2007, pages 91 - 99
RIYASAT ALI ET AL: "Genetically modified human CD4+ T cells can be evaluated in vivo without lethal graft-versus-host disease", CANCER RESEARCH, WILEY-BLACKWELL PUBLISHING LTD, GB, vol. 148, no. 4, 18 July 2016 (2016-07-18), pages 339 - 351, XP071276899, ISSN: 0019-2805, DOI: 10.1111/IMM.12613 *
SHANKARKUMAR ET AL.: "The Human Leukocyte Antigen (HLA) System", INT. J. HUM. GENET., vol. 4, no. 2, 2004, pages 91 - 103
SHULTZ ET AL., J IMMUNOL, vol. 154, 1995, pages 180 - 91
STROWIG ET AL., PROC NATL ACAD SCI, vol. 108, 2011, pages 13218 - 13223
STROWIG ET AL., PROC NATL ACAD SCI, vol. 108, no. 32, 9 August 2011 (2011-08-09), pages 13218 - 23
STROWIG TILL ET AL: "Priming of protective T cell responses against virus-induced tumors in mice with human immune system components - PMC", JOURNAL OF EXPERIMENTAL MEDICINE, vol. 206, no. 6, June 2009 (2009-06-01), US, pages 1423 - 1434, XP093298645, ISSN: 0022-1007, Retrieved from the Internet <URL:https://pmc.ncbi.nlm.nih.gov/articles/PMC2715061/> DOI: 10.1084/jem.20081720 *
VALENZUELA ET AL., NAT BIOTECHNOL., vol. 21, no. 6, June 2003 (2003-06-01), pages 652 - 9
VALENZUELA ET AL.: "High-throughput engineering of the mouse genome coupled with high-resolution expression analysis", NATURE BIOTECH, vol. 21, no. 6, 2003, pages 652 - 659

Similar Documents

Publication Publication Date Title
AU2022200302B2 (en) Genetically modified non-human animals and methods of use thereof
CN113349159B (en) Humanized T cell-mediated immune response in non-human animals
EP2770821B1 (en) Genetically modified major histocompatibility complex mice
JP2022121465A (en) Mice expressing humanized T-cell co-receptors
JP6073840B2 (en) Humanized FcγR mouse
KR20230164150A (en) Genetically modified mice containing humanized cellular immune system components with improved diversity of the TCRβ repertoire
WO2025212991A1 (en) Rodent models of disease
KR20250048155A (en) Non-human animals with humanized CLEC9A gene
HK40068456B (en) Genetically modified non-human animals and methods of use thereof
HK40111833A (en) Genetically modified non-human animals and methods of use thereof
HK40068456A (en) Genetically modified non-human animals and methods of use thereof
HK40016315A (en) Genetically modified non-human animals and methods of use thereof
HK40016315B (en) Genetically modified non-human animals and methods of use thereof
HK1253909B (en) Immunodeficient, genetically modified rodent and methods of use thereof
HK1210380B (en) Genetically modified non-human animals and methods of use thereof
HK1200272B (en) Genetically modified major histocompatibility complex mice

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 25723006

Country of ref document: EP

Kind code of ref document: A1