Abstract
Development of autoreactive CD4 T cells contributing to type 1 diabetes (T1D) in both humans and nonobese diabetic (NOD) mice is either promoted or dominantly inhibited by particular MHC class II variants. In addition, it is now clear that when co-expressed with other susceptibility genes, some common MHC class I variants aberrantly mediate autoreactive CD8 T cell responses also essential to T1D development. However, it was unknown whether the development of diabetogenic CD8 T cells could also be dominantly inhibited by particular MHC variants. We addressed this issue by crossing NOD mice transgenically expressing the TCR from the diabetogenic CD8 T cell clone AI4 with NOD stocks congenic for MHC haplotypes that dominantly inhibit T1D. High numbers of functional AI4 T cells only developed in controls homozygously expressing NOD-derived H2(g7) molecules. In contrast, heterozygous expression of some MHC haplotypes conferring T1D resistance anergized AI4 T cells through decreased TCR (H2(b)) or CD8 expression (H2(q)). Most interestingly, while AI4 T cells exert a class I-restricted effector function, H2(nb1) MHC class II molecules can contribute to their negative selection. These findings provide insights to how particular MHC class I and class II variants interactively regulate the development of diabetogenic T cells and the TCR promiscuity of such autoreactive effectors.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antigen-Presenting Cells / cytology
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Antigen-Presenting Cells / immunology
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Antigen-Presenting Cells / metabolism
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Autoantigens / immunology*
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / metabolism*
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CD8-Positive T-Lymphocytes / pathology
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Clonal Anergy / genetics
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Diabetes Mellitus, Type 1 / genetics
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Diabetes Mellitus, Type 1 / immunology*
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Diabetes Mellitus, Type 1 / pathology
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Down-Regulation / genetics
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Down-Regulation / immunology
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Female
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Genetic Carrier Screening
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Genetic Variation / immunology
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H-2 Antigens / genetics
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H-2 Antigens / immunology*
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H-2 Antigens / metabolism
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Haplotypes
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Hematopoietic Stem Cells / cytology
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Hematopoietic Stem Cells / immunology
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Hematopoietic Stem Cells / metabolism
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Histocompatibility Antigens Class II / biosynthesis
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Histocompatibility Antigens Class II / genetics
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Histocompatibility Antigens Class II / physiology*
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Histocompatibility Testing
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Lymphocyte Activation / genetics
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Male
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Mice
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Mice, Inbred NOD
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Mice, Transgenic
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Receptors, Antigen, T-Cell / biosynthesis
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Receptors, Antigen, T-Cell / genetics
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Receptors, Antigen, T-Cell / physiology
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Signal Transduction / genetics
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Signal Transduction / immunology
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T-Lymphocyte Subsets / immunology*
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T-Lymphocyte Subsets / metabolism*
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T-Lymphocyte Subsets / pathology
Substances
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Autoantigens
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H-2 Antigens
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Histocompatibility Antigens Class II
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Receptors, Antigen, T-Cell