GILT Modulates CD4 super(+) T-Cell Tolerance to the Melanocyte Differentiation Antigen Tyrosinase-Related Protein 1

• Published in: Journal of investigative dermatology Vol. 132; no. 1; pp. 154 - 162
• Main Authors: Rausch, Matthew P, Taraszka Hastings, K
• Format: Journal Article
• Language: English
• Published: 01.01.2012
• ISSN: 0022-202X
• DOI: 10.1038/jid.2011.236

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- gamma 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 super(+) T cells to induce vitiligo. Thus, GILT has a critical role in regulating CD4 super(+) T-cell tolerance to an endogenous skin-restricted antigen relevant to controlling autoimmunity and generating effective immunotherapy for melanoma.