GILT regulates CD4+ T cell tolerance (100.28)

Abstract

Abstract Regulating the balance between T cell activation and tolerance is essential for stimulating an anti-tumor immune response and in controlling autoimmunity. We have shown that gamma-interferon-inducible lysosomal thiol reductase (GILT) is required for efficient MHC class II-restricted processing of an epitope from the melanoma antigen tyrosinase-related protein 1 (TRP1). Using CD4+ TRP1-specific T cell receptor transgenic mice, here we demonstrate a novel function for GILT in the regulation of TRP1-specific T cell tolerance. TRP1-specific T cells are centrally deleted in mice expressing both GILT and TRP1 on the RAG-/- background. In contrast, CD4+ T cells develop in the absence of either GILT or TRP1. GILT’s role in central tolerance is supported by GILT and TRP1 expression in thymic stromal cells. Although TRP1-specific CD4+ T cells escape thymic deletion in the absence of GILT, they are tolerant to TRP1 and do not induce vitiligo. TRP1-specific T cells from GILT-deficient mice initially divide in response to antigen, but fail to produce substantial levels of IFN-γ and IL-2. Tolerance is partially mediated by CD25+Foxp3+ regulatory T (Treg) cells. There is an increased percentage of TRP1-specific Treg cells in GILT-deficient compared to TRP1-deficient mice, and Treg cell depletion allows GILT-deficient TRP1-specific CD4+ T cells to induce vitiligo. These studies highlight a critical role for GILT in shaping the CD4+ T cell repertoire.