Zhang Song, Takaku Motoki, Zou Liyun, Gu Ai-di, Chou Wei-Chun, Zhang Ge, Wu Bing, Kong Qing, Thomas Seddon Y, Serody Jonathan S, Chen Xian, Xu Xiaojiang, Wade Paul A, Cook Donald N, Ting Jenny P Y, Wan Yisong Y
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, North Carolina 27599, USA.
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, North Carolina 27599, USA.
Nature. 2017 Nov 2;551(7678):105-109. doi: 10.1038/nature24283. Epub 2017 Oct 25.
T helper 17 (T17) cells are critically involved in host defence, inflammation, and autoimmunity. Transforming growth factor β (TGFβ) is instrumental in T17 cell differentiation by cooperating with interleukin-6 (refs 6, 7). Yet, the mechanism by which TGFβ enables T17 cell differentiation remains elusive. Here we reveal that TGFβ enables T17 cell differentiation by reversing SKI-SMAD4-mediated suppression of the expression of the retinoic acid receptor (RAR)-related orphan receptor γt (RORγt). We found that, unlike wild-type T cells, SMAD4-deficient T cells differentiate into T17 cells in the absence of TGFβ signalling in a RORγt-dependent manner. Ectopic SMAD4 expression suppresses RORγt expression and T17 cell differentiation of SMAD4-deficient T cells. However, TGFβ neutralizes SMAD4-mediated suppression without affecting SMAD4 binding to the Rorc locus. Proteomic analysis revealed that SMAD4 interacts with SKI, a transcriptional repressor that is degraded upon TGFβ stimulation. SKI controls histone acetylation and deacetylation of the Rorc locus and T17 cell differentiation via SMAD4: ectopic SKI expression inhibits H3K9 acetylation of the Rorc locus, Rorc expression, and T17 cell differentiation in a SMAD4-dependent manner. Therefore, TGFβ-induced disruption of SKI reverses SKI-SMAD4-mediated suppression of RORγt to enable T17 cell differentiation. This study reveals a critical mechanism by which TGFβ controls T17 cell differentiation and uncovers the SKI-SMAD4 axis as a potential therapeutic target for treating T17-related diseases.
辅助性T细胞17（T17细胞）在宿主防御、炎症和自身免疫中起着关键作用。转化生长因子β（TGFβ）通过与白细胞介素-6协同作用，在T17细胞分化中发挥重要作用（参考文献6、7）。然而，TGFβ促使T17细胞分化的机制仍不清楚。在这里，我们揭示TGFβ通过逆转SKI-SMAD4介导的视黄酸受体（RAR）相关孤儿受体γt（RORγt）表达抑制来促使T17细胞分化。我们发现，与野生型T细胞不同，SMAD4缺陷型T细胞在没有TGFβ信号的情况下以RORγt依赖的方式分化为T17细胞。异位表达SMAD4可抑制SMAD4缺陷型T细胞的RORγt表达和T17细胞分化。然而，TGFβ可中和SMAD4介导的抑制作用，而不影响SMAD4与Rorc基因座的结合。蛋白质组学分析表明，SMAD4与SKI相互作用，SKI是一种转录抑制因子，在TGFβ刺激下会降解。SKI通过SMAD4控制Rorc基因座的组蛋白乙酰化和去乙酰化以及T17细胞分化：异位表达SKI以SMAD4依赖的方式抑制Rorc基因座的H3K9乙酰化、Rorc表达和T17细胞分化。因此，TGFβ诱导的SKI破坏可逆转SKI-SMADAD4介导的RORγt抑制，从而促使T17细胞分化。这项研究揭示了TGFβ控制T17细胞分化的关键机制，并发现SKI-SMAD4轴是治疗T17相关疾病的潜在治疗靶点。
