The NOD Mouse: Recessive Diabetogenic Gene in the Major Histocompatibility Complex

Hattori, Masao; Buse, John B.; Jackson, Richard A.; Glimcher, Laurie H.; Dorf, Martin E.; Minami, Manabu; Makino, Susumu; Moriwaki, Kazuo; Kuzuya, Hideshi; Imura, H; Strauss, William; Seidman, J. G.; Eisenbarth, George S.

doi:10.1126/science.3003909

Cited by 392 publications

(243 citation statements)

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“…Studies in the NOD mouse model established that both CD4 ϩ and CD8 ϩ T-cells are required for spontaneous diabetes development (1). Historically, the CD4 ϩ T-cell subset was the most intensively studied, due in part to the early association found between the expression of particular class II major histocompatibility complex (MHC) molecules and type 1 diabetes in both humans and NOD mice (2,3). However, multiple lines of investigation in NOD mice have led to a heightened appreciation for the importance of islet antigen-specific CD8…”

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confidence: 99%

In Vivo Cytotoxicity of Insulin-Specific CD8+ T-Cells in HLA-A*0201 Transgenic NOD Mice

et al. 2007

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OBJECTIVE—CD8+ T-cells specific for islet antigens are essential for the development of type 1 diabetes in the NOD mouse model of the disease. Such T-cells can also be detected in the blood of type 1 diabetic patients, suggesting their importance in the pathogenesis of the human disease as well. The development of peptide-based therapeutic reagents that target islet-reactive CD8+ T-cells will require the identification of disease-relevant epitopes. RESEARCH DESIGN AND METHODS—We used islet-infiltrating CD8+ T-cells from HLA-A*0201 transgenic NOD mice in an interferon-γ enzyme-linked immunospot assay to identify autoantigenic peptides targeted during the spontaneous development of disease. We concentrated on insulin (Ins), which is a key target of the autoimmune response in NOD mice and patients alike. RESULTS—We found that HLA-A*0201-restricted T-cells isolated from the islets of the transgenic mice were specific for Ins1 L3–11, Ins1 B5–14, and Ins1/2 A2–10. Insulin-reactive T-cells were present in the islets of mice as young as 5 weeks of age, suggesting an important function for these specificities early in the pathogenic process. Although there was individual variation in peptide reactivity, Ins1 B5–14 and Ins1/2 A2–10 were the immunodominant epitopes. Notably, in vivo cytotoxicity to cells bearing these peptides was observed, further confirming them as important targets of the pathogenic process. CONCLUSIONS—The human versions of B5–14 and A2–10, differing from the murine peptides by only a single residue, represent excellent candidates to explore as CD8+ T-cell targets in HLA-A*0201–positive type 1 diabetic patients.

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confidence: 99%

In Vivo Cytotoxicity of Insulin-Specific CD8+ T-Cells in HLA-A*0201 Transgenic NOD Mice

et al. 2007

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“…The NOD mouse has a single MHCII molecule, IA g7 , which is essential for the development of disease (8). Polymorphisms in the IA g7 β-chain (9) shape the p9 binding pocket (10,11) and contribute to a side chain preference distinct from that of other IA alleles (6).…”

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Diabetogenic T cells recognize insulin bound to IA^g7in an unexpected, weakly binding register

Stadinski

Zhang²,

Crawford

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

179

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A peptide derived from the insulin B chain contains a major epitope for diabetogenic CD4 + T cells in the NOD mouse model of type 1 diabetes (T1D). This peptide can fill the binding groove of the NOD MHCII molecule, IA g7 , in a number of ways or "registers." We show here that a diverse set of NOD anti-insulin T cells all recognize this peptide bound in the same register. Surprisingly, this register results in the poorest binding of peptide to IA g7 . The poor binding is due to an incompatibility between the p9 amino acid of the peptide and the unique IA g7 p9 pocket polymorphisms that are strongly associated with susceptibility to T1D. Our findings suggest that the association of autoimmunity with particular MHCII alleles may be do to poorer, rather than more favorable, binding of the critical self-epitopes, allowing T-cell escape from thymic deletion.T he development of type 1 diabetes (T1D) in NOD mice and humans is associated with certain alleles of MHCII (1-3). These alleles present sets of peptides distinct from those presented by other MHCII alleles (4, 5), thus their association with T1D may be because they are better than other MHCII alleles at presentation of peptides derived from pancreatic islet β-cell proteins (6). However, tests of this and other hypotheses about the role of MHCII in T1D require a precise identification of the peptides recognized by pathogenic CD4 + T cells.Peptides bind in an extended conformation to a groove of MHCII. The binding involves a nonamer of the peptide (p), in which the side chains of "anchor" amino acids at positions p1, p4, p6, and p9 interact with corresponding pockets in the groove (7). Polymorphic MHCII residues lining the binding groove influence the preference of each pocket for particular peptide side chains, providing each MHCII allele with a unique preferred peptidebinding motif that dictates the position or "register" of the peptide in the groove. However, the specificities of these pockets are not absolute, and so a peptide may bind in more than one register, with the hierarchy of registers determined by how well the pockets accept the anchor residues. The register of the peptide affects which of its side chains are pointing out of the MHCII groove and hence interaction with T cell receptors. Thus individual peptide-responsive T cells will recognize the peptide bound to MHCII in only one of the possible registers.The NOD mouse has a single MHCII molecule, IA g7 , which is essential for the development of disease (8). Polymorphisms in the IA g7 β-chain (9) shape the p9 binding pocket (10, 11) and contribute to a side chain preference distinct from that of other IA alleles (6). In particular, an Asp-to-Ser alteration at IA g7 β57 disrupts a conserved salt bridge to an Arg at α76. This allows the positively charged Arg to interact with the peptide amino acid side chain in the p9 pocket (11) and confers a unique preference for binding peptide registers with acidic residues at this position (6).The insulin B-chain peptide (B:12-23) is recognized by diabetogenic ...

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“…Of the numerous Idd loci, Idd1 is the best understood. It localizes to the H2 g7 region, the MHC of NOD mice (2)(3)(4)(5)(6). Pathogenic H2 g7 -restricted CD4 ϩ and CD8 ϩ T lymphocytes are thought to be kept under check by immune regulatory cells such as the invariant V␣14J␣18 TCR ␣-chain-positive natural T (iNKT) cells (7-9) either directly or through the mediation of other cell types (e.g., dendritic cells (10) or CD4 ϩ DX5 ϩ T lymphocytes (11).…”

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Genetic Dissection of Vα14Jα18 Natural T Cell Number and Function in Autoimmune-Prone Mice

Matsuki

Stanic

Embers

et al. 2003

The Journal of Immunology

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Nonobese diabetic (NOD) mice, a model for type I diabetes (TID), have reduced numbers of invariant Vα14Jα18 TCR α-chain-positive natural T (iNKT) cells that do not release IL-4 in response to in vivo activation through their Ag receptor. The deficit in iNKT cell number and function is implicated in immune dysregulation and the etiology of TID. Therefore, we reasoned that the genetic determinant(s) that controls iNKT cell number and function might lie within Idd (insulin-dependent diabetes susceptibility locus) regions, which are known to contain TID resistance or susceptibility genes. A systematic analysis of iNKT cell number and function in Idd congenic mice revealed that neither iNKT cell number nor their inability to rapidly secrete IL-4 in response to acute in vivo activation by Ag underlies the mechanism of protection from diabetes in Idd congenic mice. Moreover, the regulation of iNKT cell number and function appears to be under the control of several genes. The most notable of these map to the Idd4, Idd5, Idd9.1, and Idd13 regions of the mouse genome. Together these findings provide a clue to the genetic mechanism(s) underlying iNKT cell deficiency in NOD mice.

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The NOD Mouse: Recessive Diabetogenic Gene in the Major Histocompatibility Complex

Cited by 392 publications

References 20 publications

In Vivo Cytotoxicity of Insulin-Specific CD8+ T-Cells in HLA-A*0201 Transgenic NOD Mice

In Vivo Cytotoxicity of Insulin-Specific CD8+ T-Cells in HLA-A*0201 Transgenic NOD Mice

Diabetogenic T cells recognize insulin bound to IA^g7in an unexpected, weakly binding register

Genetic Dissection of Vα14Jα18 Natural T Cell Number and Function in Autoimmune-Prone Mice

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The NOD Mouse: Recessive Diabetogenic Gene in the Major Histocompatibility Complex

Cited by 392 publications

References 20 publications

In Vivo Cytotoxicity of Insulin-Specific CD8+ T-Cells in HLA-A*0201 Transgenic NOD Mice

In Vivo Cytotoxicity of Insulin-Specific CD8+ T-Cells in HLA-A*0201 Transgenic NOD Mice

Diabetogenic T cells recognize insulin bound to IAg7in an unexpected, weakly binding register

Genetic Dissection of Vα14Jα18 Natural T Cell Number and Function in Autoimmune-Prone Mice

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Diabetogenic T cells recognize insulin bound to IA^g7in an unexpected, weakly binding register