Sox5 and c-Maf cooperatively induce Th17 cell differentiation via RORγt induction as downstream targets of Stat3.
Sox5 and c-Maf cooperatively induce Th17 cell differentiation via RORγt induction as downstream targets of Stat3.
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DOI：
10.1084/jem.20130791
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发表时间：
2014-08-25
期刊：
影响因子：
--
通讯作者：
Nakajima H
中科院分区：
文献类型：
--
作者：
Tanaka S;Suto A;Iwamoto T;Kashiwakuma D;Kagami S;Suzuki K;Takatori H;Tamachi T;Hirose K;Onodera A;Suzuki J;Ohara O;Yamashita M;Nakayama T;Nakajima H
Sox 5、Sox 5 t和c-Maf的一种新型同种型激活RORγt以诱导Th 17细胞。Sox 5 −/−小鼠表现出受损的Th 17分化，因此对EAE和迟发型超敏反应具有抗性。Stat 3信号传导对于RORγt的诱导和随后的Th 17细胞分化是必需的。然而，Stat 3下游的RORγt表达靶点仍然很大程度上未知。我们在这里表明，一种新的同种型Sox 5，命名为Sox 5 t，诱导在Th 17细胞中的Stat 3依赖的方式。在体内，T细胞特异性Sox 5缺陷小鼠表现出受损的Th 17细胞分化，并对实验性自身免疫性脑脊髓炎和迟发型超敏反应具有抗性。逆转录病毒介导的Sox 5和c-Maf诱导Th 17细胞分化，即使在Stat 3缺陷型CD 4 + T细胞中也是如此，但在RORγ t缺陷型CD 4 + T细胞中则不然，这表明Sox 5和c-Maf作为Stat 3的下游效应物和RORγt的上游诱导物诱导Th 17细胞分化。此外，Sox 5通过其HMG结构域和c-Maf的DNA结合结构域与c-Maf物理结合，并且Sox 5与c-Maf一起直接激活CD 4 + T细胞中的RORγt启动子。总的来说，我们的结果表明，Sox 5和c-Maf通过诱导作为Stat 3下游靶点的RORγt协同诱导Th 17细胞分化。
A novel isoform of Sox5, Sox5t, and c-Maf activate RORγt to induce Th17 cells. Sox5−/− mice exhibit impaired Th17 differentiation and are thus resistant to EAE and delayed-type hypersensitivity. Stat3 signaling is essential for the induction of RORγt and subsequent Th17 cell differentiation. However, the downstream targets of Stat3 for RORγt expression remain largely unknown. We show here that a novel isoform of Sox5, named Sox5t, is induced in Th17 cells in a Stat3-dependent manner. In vivo, T cell–specific Sox5-deficient mice exhibit impaired Th17 cell differentiation and are resistant to experimental autoimmune encephalomyelitis and delayed-type hypersensitivity. Retrovirus-mediated induction of Sox5 together with c-Maf induces Th17 cell differentiation even in Stat3-deficient CD4+ T cells but not in RORγt-deficient CD4+ T cells, indicating that Sox5 and c-Maf induce Th17 cell differentiation as downstream effectors of Stat3 and as upstream inducers of RORγt. Moreover, Sox5 physically associates with c-Maf via the HMG domain of Sox5 and DNA-binding domain of c-Maf, and Sox5 together with c-Maf directly activates the promoter of RORγt in CD4+ T cells. Collectively, our results suggest that Sox5 and c-Maf cooperatively induce Th17 cell differentiation via the induction of RORγt as downstream targets of Stat3.
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