Cutting edge: developmental up-regulation of IFN-gamma-inducible lysosomal thiol reductase expression leads to reduced T cell sensitivity and less severe autoimmunity.
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.
Maric
Maja
M
Department of Microbiology and Immunology, Georgetown University School of Medicine, Washington, DC 20057, USA. mam254@georgetown.edu
Barjaktarevic
Igor
I
Bogunovic
Branka
B
Stojakovic
Milica
M
Maric
Christine
C
Vukmanovic
Stanislav
S
D000818:Animals; D001327:Autoimmune Diseases / Q000201:enzymology / Q000276:immunology* / Q000517:prevention & control*; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000276:immunology* / Q000628:therapy; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D018507:Gene Expression Regulation, Developmental / Q000276:immunology*; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology; D006943:Hyperglycemia / Q000201:enzymology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010088:Oxidoreductases / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D050862:Oxidoreductases Acting on Sulfur Group Donors; D012720:Severity of Illness Index; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*; D000099156:Superoxide Dismutase 2
D010088:Oxidoreductases; D050862:Oxidoreductases Acting on Sulfur Group Donors; D013482:Superoxide Dismutase; D013481:Superoxides; D000099156:Superoxide Dismutase 2; C483811:Ifi30 protein, mouse