Molecular Immunology Section, National Eye Institute, National Institutes of Health, Bethesda, MD 20892.
J Immunol. 2013 Nov 15;191(10):5036-43. doi: 10.4049/jimmunol.1301132. Epub 2013 Oct 7.
Suppressors of cytokine signaling (SOCS) proteins are negative-feedback regulators of the JAK/STAT pathway, and SOCS3 contributes to host immunity by regulating the intensity and duration of cytokine signals and inflammatory responses. Mice with Socs3 deletion in myeloid cells exhibit enhanced STAT3 signaling, expansion of Th1 and Th17 cells, and develop severe experimental autoimmune encephalomyelitis. Interestingly, development of the unique IL-17/IFN-γ double-producing (Th17/IFN-γ and Tc17/IFN-γ) subsets that exhibit strong cytotoxic activities and are associated with pathogenesis of several autoimmune diseases has recently been shown to depend on epigenetic suppression of SOCS3 expression, further suggesting involvement of SOCS3 in autoimmunity and tumor immunity. In this study, we generated mice with Socs3 deletion in the CD4 T cell compartment (CD4-SOCS3 knockout [KO]) to determine in vivo effects of the loss of Socs3 in the T cell-mediated autoimmune disease, experimental autoimmune uveitis (EAU). In contrast to the exacerbation of experimental autoimmune encephalomyelitis in myeloid-specific SOCS3-deleted mice, CD4-SOCS3KO mice were protected from acute and chronic uveitis. Protection from EAU correlated with enhanced expression of CTLA-4 and expansion of IL-10-producing regulatory T cells with augmented suppressive activities. We further show that SOCS3 interacts with CTLA-4 and negatively regulates CTLA-4 levels in T cells, providing a mechanistic explanation for the expansion of regulatory T cells in CD4-SOCS3 during EAU. Contrary to in vitro epigenetic studies, Th17/IFN-γ and Tc17/IFN-γ populations were markedly reduced in CD4-SOCS3KO, suggesting that SOCS3 promotes expansion of the Th17/IFN-γ subset associated with development of severe uveitis. Thus, SOCS3 is a potential therapeutic target in uveitis and other autoinflammatory diseases.
细胞因子信号转导抑制蛋白（SOCS）是 JAK/STAT 通路的负反馈调节因子，SOCS3 通过调节细胞因子信号和炎症反应的强度和持续时间来促进宿主免疫。髓细胞中 Socs3 缺失的小鼠表现出 STAT3 信号增强、Th1 和 Th17 细胞扩增，并发展出严重的实验性自身免疫性脑脊髓炎。有趣的是，最近已经表明，具有强大细胞毒性活性并与几种自身免疫性疾病发病机制相关的独特的 IL-17/IFN-γ 双产生（Th17/IFN-γ 和 Tc17/IFN-γ）亚群的发育依赖于 SOCS3 表达的表观遗传抑制，进一步表明 SOCS3 参与自身免疫和肿瘤免疫。在这项研究中，我们生成了 CD4 T 细胞区室中 Socs3 缺失的小鼠（CD4-SOCS3 敲除 [KO]），以确定 T 细胞介导的自身免疫性疾病，实验性自身免疫性葡萄膜炎（EAU）中 Socs3 缺失的体内影响。与髓系特异性 SOCS3 缺失小鼠中实验性自身免疫性脑脊髓炎的加重相反，CD4-SOCS3KO 小鼠从急性和慢性葡萄膜炎中得到保护。从 EAU 得到保护与 CTLA-4 的表达增强以及具有增强的抑制活性的 IL-10 产生调节性 T 细胞的扩增相关。我们进一步表明，SOCS3 与 CTLA-4 相互作用并负调节 T 细胞中的 CTLA-4 水平，为 CD4-SOCS3 在 EAU 期间调节性 T 细胞的扩增提供了一种机制解释。与体外表观遗传研究相反，在 CD4-SOCS3KO 中，Th17/IFN-γ 和 Tc17/IFN-γ 群体明显减少，表明 SOCS3 促进了与严重葡萄膜炎发展相关的 Th17/IFN-γ 亚群的扩增。因此，SOCS3 是葡萄膜炎和其他自身炎症性疾病的潜在治疗靶点。
