Cutting Edge: Developmental Up-Regulation of Ifn--Inducible Lysosomal Thiol Reductase Expression Leads to Reduced T Cell Sensitivity and Less Severe Autoimmunity

Maric, M.; Barjaktarevic, I.; Bogunovic, B.; Stojakovic, M.; Maric, C.; Vukmanovic, S.

The Journal of Immunology 182(2): 746-750


DOI: 10.4049/jimmunol.182.2.746
Accession: 068491236

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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.