Melanoma Antigen Tyrosinase - Related GILT Accelerates Autoimmunity to the Hastings

Melanocyte differentiation Ags, including tyrosinase-related protein (TRP) 1, are relevant to both autoimmune skin depigmentation (vitiligo) and tumor immunity, because they are expressed by both benign melanocytes and many malignant melanomas. Melanoma patients generate CD4 + T cells that specifically recognize these proteins. TRP1 contains internal disulfide bonds and is presented by MHC class II molecules. g-IFN–inducible lysosomal thiol reductase (GILT) facilitates the generation of class II-binding peptides by the endocytic reduction of protein disulfide bonds. We show in this study that GILT is required for efficient MHC class II-restricted processing of a TRP1 epitope in vitro and accelerates the onset of vitiligo in TRP1-specific TCR transgenic mice. The presence of GILT confers a small increase in the percentage of autoreactive T cells with an effector memory phenotype that may contribute to earlier disease onset. The onset of vitiligo is associated with a greater increase in the percentage of autoreactive T cells with an effector memory phenotype. Given that many self and tumor Ags have disulfide bonds and are presented on MHC class II, GILT is likely to be important in the pathogenesis of other CD4 + T cell-mediated autoimmune diseases and for the development of effective cancer immunotherapy. G amma-IFN inducible lysosomal thiol reductase (GILT) is expressed in APCs, where it localizes to MHC class II-loading compartments (1–5). Its expression can be induced by IFN-g in other cell types, including melanomas (1, 4, 6). GILT is synthesized as a precursor and targeted via the mannose-6 phosphate receptor to the endocytic pathway where N-and C-terminal propeptides are removed to generate the mature form (7) found in multivesicular late endosomes and multilamellar lysosomes (1, 5). A minor amount of enzymatically active precursor is secreted as a disulfide-linked dimer (7). A thioredoxin-like CXXC motif constitutes the active site (1) of the enzyme, which facilitates the generation of MHC class II-restricted epitopes from disulfide bond-containing Ags, such as hen egg lysozyme (HEL), HIV-1 envelope protein, and a cysteinylated peptide from Ig k (5, 6, 8, 9). Despite the fact that not all HEL epitopes are dependent on GILT, the CD4 + T cell recall response to HEL in GILT 2/2 mice is about one-tenth of that seen in wild-type mice (5). Similar reductions in recall responses are seen upon immunization with other Ags containing disulfide bonds (5). Melanocyte differentiation Ags, such as tyrosinase, tyrosinase-related protein (TRP) 1 (also called gp75), and TRP2, are …