Abstract
Tuning of TCR-mediated activation was demonstrated to be critical for lineage fate in T cell development, as well as in the control of autoimmunity. In this study, we identify a novel diabetes susceptibility gene, Idd28, in the NOD mouse and provide evidence that Cd3zeta (Cd247) constitutes a prime candidate gene for this locus. Moreover, we show that the allele of the Cd3zeta gene expressed in NOD and DBA/2 mouse strains confers lower levels of T cell activation compared with the allele expressed by C57BL/6 (B6), BALB/c, and C3H/HeJ mice. These results support a model in which the development of autoimmune diabetes is dependent on a TCR signal mediated by a less-efficient NOD allele of the Cd3zeta gene.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Alleles
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Animals
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Antigens, CD / genetics
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Antigens, CD / metabolism
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CD3 Complex / genetics*
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CD3 Complex / physiology
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CTLA-4 Antigen
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Cells, Cultured
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Cytokines / biosynthesis
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Cytokines / deficiency
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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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Female
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Genetic Predisposition to Disease
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Genetic Variation / immunology*
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Growth Inhibitors / genetics
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Growth Inhibitors / physiology
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Inflammation / genetics
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Inflammation / immunology
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Inflammation / pathology
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Lymphocyte Activation / genetics*
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Lymphocyte Activation / immunology
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Mice
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Mice, Congenic
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Mice, Inbred BALB C
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Mice, Inbred C3H
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Mice, Inbred C57BL
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Mice, Inbred DBA
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Mice, Inbred NOD
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Species Specificity
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T-Lymphocyte Subsets / immunology*
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T-Lymphocyte Subsets / metabolism
Substances
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Antigens, CD
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CD3 Complex
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CD3 antigen, zeta chain
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CTLA-4 Antigen
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Ctla4 protein, mouse
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Cytokines
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Growth Inhibitors