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

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-γ-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.

Disulfide Reduction in the Endocytic Pathway: Immunological Functions of Gamma-Interferon-Inducible Lysosomal Thiol Reductase

“…Similarly, GILT decreases proliferation and cytotoxic activity in T cells (5). GILT expression levels increase with T cell development from double-positive to single-positive thymocytes to peripheral T cells (37), and this may serve as a mechanism to regulate T cell sensitivity to self-antigens. In fact, GILT À=À mice develop earlier and more severe hyperglycemia in streptozotocin-induced diabetes, a CD8 þ T cell-mediated model of autoimmunity, which shows that GILT serves to diminish autoimmunity independent of its role in MHC class II-restricted processing (37).…”

“…GILT is constitutively expressed in most APCs, including monocytes=macrophages, B cells (primary and cell lines), and bone-marrow derived DCs (3,25,29,30,34,36). GILT is also constitutively expressed in thymocytes (37), mature T cells (5,37), and some fibroblasts (9,64). IFN-g plays an important role in inducing expression of MHC class II and other components of the class II-restricted processing pathway, including Ii and HLA-DM (10).…”

Mitochondria as Oxidative Signaling Organelles in T-cell Activation: Physiological Role and Pathological Implications

“…However, at a later stage (4-8 h after TCR stimulation), increased MnSOD levels diminish the oxidative signal (probably due to an out-titration effect) (Kaminski et al 2012a). Reports by Case et al (2011) and Maric et al (2009) support a crucial role of MnSOD for T-cell homeostasis. T-cell-specific MnSOD knock-out results in increased mitochondrial superoxide anion levels, enhanced thymocyte apoptosis, decreased number of peripheral T cells and impaired clearance of an influenza virus.…”

“…Both thymocytes and peripheral T cells appear hyperactivated (Case et al 2011). Decreased MnSOD activity and content in mouse T cells deficient in the interferon (IFN)-c-inducible lysosomal thiol reductase (Gilt -/-) lead to enhanced TCR-triggered ERK activation and higher intracellular superoxide levels (Maric et al 2009). Of note, T lymphocyte activation up-regulates expression and content of the uncoupling protein 2 (UCP2), an exclusively mitochondrial matrix protein of possible anti-oxidative/ uncoupling function, yet another negative regulator of mitochondrial ROS release (Degasperi et al 2006;Rupprecht et al 2012).…”

Molecular cloning, expression and functional analysis of ISG15 in orange-spotted grouper, Epinephelus coioides

“…Given that many self and tumor antigens have disulfide bonds and are presented on MHC class II, GILT is likely to be important in the pathogenesis of other CD4 þ T cell-mediated autoimmune diseases and for the development of effective cancer immunotherapy [12]. Current studies suggest that developmental up-regulation of human GILT expression leads to reduced T cell sensitivity and less severe autoimmunity [13].…”