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Gamma-interferon-inducible lysosomal thiol reductase (GILT) facilitates MHC class II-restricted processing though 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 repector transgenic mice, we identify a novel role 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 four-fold increase in the percentage of TRP1-specific regulatory T cells compared to TRP1-deficient mice, and depletion of regulatory T cells partially restores the ability of GILT-deficient TRP1-specific CD4+ T cells to induce vitiligo. Thus, GILT plays 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.