Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; College of Life Sciences, Nankai University, 300071 Tianjin, China.
Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Immunology, Dalian Medical University, Dalian 116044, China.
Mol Immunol. 2019 Oct;114:260-268. doi: 10.1016/j.molimm.2019.07.029. Epub 2019 Aug 6.
Th17 cells are essential for the pathogenesis of inflammatory and autoimmune diseases. In the presence of TGF-β, the differentiation of Th17 cells can be induced by inflammatory cytokines, especially IL-6, which is mainly produced by antigen presenting cells (APCs); or IL-21, which is derived from T cells. IL-21 is required for IL-6-induced Th17 cell differentiation. However, the key regulators and underlying mechanisms for IL-21-induced Th17 differentiation is still elusive. Here we show that SMAD4 is a key regulator in IL-21-induced Th17 differentiation. SMAD4 deficient naïve T cells can differentiate into Th17 cells in the absence of TGF-β signaling, and these Th17 cells are pathogenic during EAE. SMAD4 represses Rorc mRNA transcription to constrain IL-21-induced Th17 differentiation in the absence of TGF-β signaling. While in the presence of TGF-β, SMAD4 losses its suppressive ability due to the degradation of SKI. Mutation of Y429A or A432E on SMAD4 disrupts the interaction of SKI from SMAD4 and eliminates SMAD4 mediated suppression of Th17 differentiation. SMAD4 is indispensable for SKI binding to Rorc promoter region to regulate Th17 differentiation. Moreover, activin can induce Th17 differentiation in combination with IL-21, and the process is also subjected to the control of SKI and SMAD4. This study therefore elucidates critical mechanism for IL-21-induced Th17 differentiation to indicate SKI and SMAD4 as potential therapeutic targets for treating autoimmune diseases.
Th17 细胞对于炎症性和自身免疫性疾病的发病机制至关重要。在 TGF-β存在的情况下，Th17 细胞的分化可以被炎症细胞因子诱导，尤其是主要由抗原呈递细胞（APCs）产生的 IL-6；或者由 T 细胞产生的 IL-21。IL-21 是 IL-6 诱导 Th17 细胞分化所必需的。然而，IL-21 诱导 Th17 分化的关键调节因子和潜在机制仍不清楚。在这里，我们表明 SMAD4 是 IL-21 诱导 Th17 分化的关键调节因子。SMAD4 缺陷的初始 T 细胞在缺乏 TGF-β信号的情况下可以分化为 Th17 细胞，并且这些 Th17 细胞在 EAE 期间具有致病性。SMAD4 抑制 Rorc mRNA 的转录，以限制在缺乏 TGF-β信号的情况下 IL-21 诱导的 Th17 分化。而在 TGF-β存在的情况下，SMAD4 由于 SKI 的降解而失去其抑制能力。SMAD4 的 Y429A 或 A432E 突变会破坏 SKI 与 SMAD4 的相互作用，并消除 SMAD4 对 Th17 分化的介导抑制。SMAD4 对于 SKI 结合到 Rorc 启动子区域以调节 Th17 分化是不可或缺的。此外，激活素可以与 IL-21 一起诱导 Th17 分化，这个过程也受到 SKI 和 SMAD4 的控制。因此，这项研究阐明了 IL-21 诱导 Th17 分化的关键机制，表明 SKI 和 SMAD4 可能是治疗自身免疫性疾病的潜在治疗靶点。
