Msn家族激酶在Th17细胞分化及自身免疫炎症中的功能及机制研究

Th17 cells is a newly discovered pro-inflammatory helper T cell subset which secrete IL-17A, IL-17F and IL-22. Th17 cells are involved in protection against microbial infections, as well as the initiation of numerous autoimmune diseases. The studies on the molecular mechanism of Th17 cells differentiation will further our understanding in the host defense mechanisms and the pathogenesis of related autoimmune diseases . Previous studies in our lab revealed a regulatory role of MINK1 kinase in Th17 cell differentiation. The deletion of Mink1 gene in mice led to enhanced Th17 differentiation and increased susceptibility to autoimmune diseases. We’ve also been able to show that MINK1 could regulate the activation of SMAD2 through direct phosphorylation of a newly identified phosphorylation site T324, thus affecting the activation of TGF-β signaling pathway and related biological effects. This proposal will focus on the further study of the underlying mechanism of this regulation, the role of all three Msn family kinases in Th17 cell differentiation, and the pathogenesis of related inflammatory autoimmune diseases.

以分泌IL-17A, IL-17F和IL-22为主的Th17细胞，是新近发现不同于Th1和Th2细胞的一类致炎性Th细胞。Th17细胞在抵抗胞外细菌、真菌感染的宿主防御中起重要作用，同时也是众多自身免疫性疾病的启动细胞。有关Th17细胞分化的机制研究，将帮助我们进一步了解机体的宿主防御和自身免疫性疾病发病的机制。本课题组在前期研究工作中发现Msn家族激酶MINK1能抑制Th17细胞分化：小鼠中Mink1基因缺失导致Th17分化增多和对炎症性自身免疫性疾病易感性增加；进一步研究显示MINK1主要通过调控SMAD2蛋白上T324位点磷酸化来调节SMAD2的活化，从而影响TGF-β信号通路的激活及相关生物学效应。本课题将在进一步明确MINK1作用机制的基础上，重点研究MINK1激酶所属Msn家族激酶在Th17细胞分化和相关炎症性自身免疫性疾病发病过程中的作用及机制。

Th17细胞在抵抗胞外细菌、真菌感染的宿主防御中起到重要作用，同时也是众多自身免疫性疾病的启动细胞。本项目在前期研究的基础上主要关注Msn家族激酶及其催化的磷酸化在Th17分化中的作用和机制。发现Msn家族激酶MINK1能抑制Th17细胞分化，小鼠中MINK1基因缺失导致Th17分化增多和对炎症性自身免疫性疾病易感性增加。项目完成了机制的探讨，明确了MINK1主激酶要通过调控SMAD2蛋白上T324位点磷酸化来调节SMAD2的活化，从而影响TGF-β信号通路的激活及Th17的分化。研究还明确了活性氧自由基ROS是MINK1活化的上游信号，以及PP2A是拮抗MINK1激酶活性的主要磷酸酶，在Th17分化过程中起到促进的作用。这些研究丰富了我们对Th17分化调控的认识，有助于我们进一步了解机体的宿主防御和自身免疫性疾病发病的机制。