Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China.
Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
Nat Commun. 2017 Feb 1;8:14275. doi: 10.1038/ncomms14275.
Although the differentiation of CD4T cells is widely studied, the mechanisms of antigen-presenting cell-dependent T-cell modulation are unclear. Here, we investigate the role of dendritic cell (DC)-dependent T-cell differentiation in autoimmune and antifungal inflammation and find that mammalian sterile 20-like kinase 1 (MST1) signalling from DCs negatively regulates IL-17 producing-CD4T helper cell (Th17) differentiation. MST1 deficiency in DCs increases IL-17 production by CD4T cells, whereas ectopic MST1 expression in DCs inhibits it. Notably, MST1-mediated DC-dependent Th17 differentiation regulates experimental autoimmune encephalomyelitis and antifungal immunity. Mechanistically, MST1-deficient DCs promote IL-6 secretion and regulate the activation of IL-6 receptor α/β and STAT3 in CD4T cells in the course of inducing Th17 differentiation. Activation of the p38 MAPK signal is responsible for IL-6 production in MST1-deficient DCs. Thus, our results define the DC MST1-p38MAPK signalling pathway in directing Th17 differentiation.
虽然 CD4T 细胞的分化已得到广泛研究，但抗原呈递细胞依赖性 T 细胞调节的机制尚不清楚。在这里，我们研究了树突状细胞（DC）依赖性 T 细胞分化在自身免疫和抗真菌炎症中的作用，发现哺乳动物 sterile 20-like kinase 1（MST1）信号从 DC 负调节产生白细胞介素-17（IL-17）的-CD4T 辅助细胞（Th17）分化。DC 中的 MST1 缺陷增加了 CD4T 细胞中 IL-17 的产生，而 DC 中异位 MST1 表达则抑制了它。值得注意的是，MST1 介导的 DC 依赖性 Th17 分化调节实验性自身免疫性脑脊髓炎和抗真菌免疫。从机制上讲，MST1 缺陷型 DC 在诱导 Th17 分化过程中促进 IL-6 的分泌，并调节 CD4T 细胞中 IL-6 受体 α/β和 STAT3 的激活。p38MAPK 信号的激活负责 MST1 缺陷型 DC 中 IL-6 的产生。因此，我们的研究结果定义了 DC MST1-p38MAPK 信号通路在指导 Th17 分化中的作用。
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