Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Front Immunol. 2021 Jul 15;12:707899. doi: 10.3389/fimmu.2021.707899. eCollection 2021.
Pathogenic Th17 cells are critically involved in many autoimmune diseases, while non-pathogenic Th17 cells are more immune regulatory. Understanding the mechanisms of the induction and maintenance of pathogenic Th17 cells will benefit the development of therapeutic treatments of related diseases. We have shown that the transforming growth factor-β (TGFβ) induced SKI degradation and dissociation from Smad4 complex is a prerequisite for TGFβ-induced Th17 cell differentiation. However, it is unclear whether and how SKI regulates pathogenic Th17 differentiation, which does not require TGFβ cytokine. Here we showed that SKI expression was downregulated during pathogenic Th17 cell differentiation and the ectopic expression of SKI abrogated the differentiation of pathogenic Th17 cells. Functionally, using a knock-in mouse model, we found ectopic SKI expression specifically in T cells prevented myelin oligodendrocyte glycoprotein peptide (MOG) induced experimental autoimmune encephalomyelitis (EAE), an animal model of human multiple sclerosis. We further revealed that induced SKI expression in already differentiated pathogenic Th17 cells reduced the maintenance of Th17 program and ameliorated EAE in an adoptive T cell transfer model. Therefore, our study provides valuable insights of targeting SKI to modulate pathogenic Th17 cell function and treat Th17-related diseases.
致病性 Th17 细胞在许多自身免疫性疾病中起着至关重要的作用，而非致病性 Th17 细胞具有更强的免疫调节作用。了解致病性 Th17 细胞的诱导和维持机制将有助于开发相关疾病的治疗方法。我们已经表明，转化生长因子-β（TGFβ）诱导的 SKI 降解和与 Smad4 复合物的解离是 TGFβ诱导 Th17 细胞分化的必要条件。然而，SKI 是否以及如何调节不需要 TGFβ细胞因子的致病性 Th17 分化尚不清楚。在这里，我们发现在致病性 Th17 细胞分化过程中 SKI 的表达下调，并且 SKI 的异位表达阻断了致病性 Th17 细胞的分化。功能上，我们使用一种敲入小鼠模型发现，T 细胞中特异性异位表达 SKI 可预防髓鞘少突胶质细胞糖蛋白肽（MOG）诱导的实验性自身免疫性脑脊髓炎（EAE），这是人类多发性硬化症的动物模型。我们进一步揭示，在已经分化的致病性 Th17 细胞中诱导 SKI 的表达降低了 Th17 程序的维持，并在过继性 T 细胞转移模型中改善了 EAE。因此，我们的研究为靶向 SKI 调节致病性 Th17 细胞功能和治疗 Th17 相关疾病提供了有价值的见解。
