title: GILT modulates CD4+ T-cell tolerance to the melanocyte differentiation antigen tyrosinase-related protein 1.
abstract: Gamma-IFN-inducible lysosomal thiol reductase (GILT) facilitates major histocompatibility complex class II-restricted processing through endocytic reduction of protein disulfide bonds and is necessary for efficient class II-restricted processing of melanocyte differentiation antigen, tyrosinase-related protein 1 (TRP1). Using class II-restricted, TRP1-specific T-cell receptor transgenic mice, we identify a role, to our knowledge, previously unreported, for GILT in the maintenance of tolerance to TRP1. TRP1-specific thymocytes are centrally deleted in the presence of GILT and TRP1. In contrast, CD4 single-positive thymocytes and peripheral T cells develop in the absence of GILT or TRP1, demonstrating that GILT is required for negative selection of TRP1-specific thymocytes. Although TRP1-specific T cells escape thymic deletion in the absence of GILT, they are tolerant to TRP1 and do not induce vilitigo. TRP1-specific T cells that develop in the absence of GILT have diminished IL-2 and IFN-γ production. Furthermore, GILT-deficient mice have a 4-fold increase in the percentage of TRP1-specific regulatory T (Treg) cells compared with TRP1-deficient mice, and depletion of Treg cells partially restores the ability of GILT-deficient TRP1-specific CD4(+) T cells to induce vitiligo. Thus, GILT has a critical role in regulating CD4(+) T-cell tolerance to an endogenous skin-restricted antigen relevant to controlling autoimmunity and generating effective immunotherapy for melanoma.
authors.affiliation: Department of Basic Medical Sciences, College of Medicine Phoenix, University of Arizona, Phoenix, Arizona 85004, USA.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Rausch
authors.forename: K Taraszka
authors.initials: KT
authors.lastname: Hastings
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000628:therapy; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D008545:Melanoma / Q000276:immunology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010088:Oxidoreductases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D050862:Oxidoreductases Acting on Sulfur Group Donors; D012878:Skin Neoplasms / Q000276:immunology / Q000628:therapy; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology; D014407:Tumor Cells, Cultured; D014820:Vitiligo / Q000276:immunology* / Q000473:pathology
chemical_list: D016207:Cytokines; D018398:Homeodomain Proteins; C064658:RAG-1 protein; D010088:Oxidoreductases; C064056:tyrosinase-related protein-1; C483811:Ifi30 protein, mouse; D050862:Oxidoreductases Acting on Sulfur Group Donors