Abstract
Reactivity to self-peptide/MHC complexes is required for selection of the TCR repertoire in the thymus but can also promote autoimmunity. Reduced TCR sensitivity of mature T cells is thought to help control the autoreactivity in peripheral T cells. The molecular basis for reduced sensitivity of peripheral T cells is not known. We found that peripheral T cells, but not immature thymocytes, lacking IFN-gamma-inducible lysosomal thiol reductase (GILT) display increased sensitivity to TCR ligation. GILT-/- peripheral T cells express reduced levels of mitochondrial superoxide dismutase 2 and consequently display higher levels of reactive oxygen radicals and ERK1/2 phosphorylation following activation. The increased sensitivity of GILT-deficient T cells results in a more severe hyperglycemia associated with streptozotocin-induced diabetes. GILT expression levels progressively increase in T cells with maturation. These data suggest that regulation of GILT expression may be a mechanism of T cell differentiation-associated changes in sensitivity to TCR engagement.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Autoimmune Diseases / enzymology
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Autoimmune Diseases / immunology*
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Autoimmune Diseases / prevention & control*
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Cells, Cultured
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Diabetes Mellitus, Experimental / enzymology
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Diabetes Mellitus, Experimental / immunology*
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Diabetes Mellitus, Experimental / therapy
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Down-Regulation / genetics
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Down-Regulation / immunology*
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Gene Expression Regulation, Developmental / immunology*
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Gene Expression Regulation, Enzymologic / immunology
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Hyperglycemia / enzymology
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Hyperglycemia / immunology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Oxidoreductases / biosynthesis*
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Oxidoreductases / deficiency
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Oxidoreductases / genetics
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Oxidoreductases Acting on Sulfur Group Donors
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Severity of Illness Index
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Superoxide Dismutase / antagonists & inhibitors
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Superoxide Dismutase / metabolism
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Superoxides / metabolism
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T-Lymphocyte Subsets / enzymology
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T-Lymphocyte Subsets / immunology*
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T-Lymphocyte Subsets / metabolism
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Up-Regulation / genetics
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Up-Regulation / immunology*
Substances
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Superoxides
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Oxidoreductases
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Superoxide Dismutase
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superoxide dismutase 2
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Ifi30 protein, mouse
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Oxidoreductases Acting on Sulfur Group Donors