Department of Basic Medical Sciences, College of Medicine Phoenix, University of Arizona, Phoenix, Arizona 85004, USA.
J Invest Dermatol. 2012 Jan;132(1):154-62. doi: 10.1038/jid.2011.236. Epub 2011 Aug 11.
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.
γ-干扰素诱导的溶酶体硫醇还原酶（GILT）通过内体还原蛋白二硫键促进主要组织相容性复合体 II 类限制的加工，并且对于黑素细胞分化抗原酪氨酸酶相关蛋白 1（TRP1）的有效 II 类限制加工是必需的。使用 II 类限制的、TRP1 特异性 T 细胞受体转基因小鼠，我们确定了 GILT 在维持 TRP1 耐受中的作用，据我们所知，这是以前未报道过的。TRP1 特异性胸腺细胞在 GILT 和 TRP1 的存在下被中央删除。相比之下，在没有 GILT 或 TRP1 的情况下，CD4 单阳性胸腺细胞和外周 T 细胞发育，表明 GILT 是 TRP1 特异性胸腺细胞阴性选择所必需的。尽管 TRP1 特异性 T 细胞在没有 GILT 的情况下逃避胸腺删除，但它们对 TRP1 耐受并且不会诱导白癜风。在没有 GILT 的情况下发育的 TRP1 特异性 T 细胞产生的 IL-2 和 IFN-γ 减少。此外，与 TRP1 缺陷型小鼠相比，缺乏 GILT 的小鼠中 TRP1 特异性调节性 T（Treg）细胞的百分比增加了 4 倍，并且耗尽 Treg 细胞部分恢复了缺乏 GILT 的 TRP1 特异性 CD4（+）T 细胞诱导白癜风的能力。因此，GILT 在调节 CD4（+）T 细胞对与控制自身免疫和产生黑色素瘤有效免疫疗法相关的内源性皮肤限制抗原的耐受中具有关键作用。
