Th17细胞分化中的表观遗传调节机制

Th17 cells were discovered by us as well as others 10 years ago as a new type of immune cells; abnormal Th17 response has been clinically proved to be linked to many human autoimmune diseases. Our studies and others showed that IL-6 and TGF-β play a critical role in initiating the differentiation of Th17 cells, whereas the expression of effector cytokine IL-17 is directly controlled the master transcription factor RORγt. In addition, our lab and others also demonstrated the presence of lineage-specific epigenetic modifications during Th17 cell differentiation and development. Despite these studies, however, how these cytokines and transcription factors regulate the Th17 cell-specific epigenetic mechanisms is not yet clear. .In the preliminary studies, we found that several chromatin remodeling regulatory proteins and co-activator, including Trim28, Trim33 and SRC2, are indispensable for IL-17 expression in Th17 cells in in vitro culture system. In this study, we will systematically examine the role and underlying mechanisms by which cytokines and transcription factors, through these epigenetic regulators, establish and maintain Th17-specific epigenetic programs. We will take advantage of available (conditional) gene knockout mice and high-throughput next-generation DNA sequencing technology. This study will reveal potential novel drug targets in developing therapeutics against Th17-related autoimmune diseases.

Th17细胞是10年前我们和其他实验室共同发现的一类免疫细胞，Th17的异常反应时已经在临床被证明是导致自身免疫疾病发生的关键性原因。我们和他人的研究表明Th17细胞的分化发育由IL-6和TGF-β信号启动，其效应细胞因子IL-17的表达则直接受转录因子RORγｔ调控。此外我们和其他实验室还证明Th17细胞分化过程中伴随着谱系特性的表观遗传修饰，但是这些细胞因子和相关转录因子如何调节Th17细胞特异性的表观遗传机制，尚缺乏系统的研究。.在前期工作中，我们发现一些表观遗传调节蛋白和共激活因子如Trim28、Trim33、SRC2等对Th17的分化发育有重要作用。本项目将充分利用多种（条件性）基因敲除小鼠和高通量测序技术，深入研究细胞因子、转录因子如何通过表观遗传调节蛋白在Th17细胞中确立、维持和调节其特异的表观遗传机制。本研究将有望为治疗Th17细胞相关的种种免疫性疾病提供新的药物靶点

Th17细胞是2005年由我们和其他实验室共同发现的一类新型T细胞亚群。Th17细胞的异常应答在临床上已被证明是导致人类自身免疫病的关键原因。Th17细胞的分化发育由IL-6和TGF-β信号启动，RORγｔ则控制其效应细胞因子IL-17的表达。我们和他人的研究表明，Th17细胞分化还伴随着谱系特异性的表观遗传修饰，但调控机制尚不明确。在本项目，通过借助高通量测序技术、基因敲除小鼠和多种疾病模型，我们深入研究了细胞因子、转录因子、表观调控蛋白在Th17细胞分化及相关自身免疫疾病中的功能和调控机制，取得了系列重要进展与发现。譬如发现IL-6和TGF-β启动Rorc表达及早期Th17分化的转录与表观协同机制（Immunity,2020);发现调控RORγt招募和Th17细胞分化的关键表观调控蛋白TRIM28 (Nature Communications，2018); 发现TRIM33以表观方式调控Il17/Il10表达和Th17致病性（JEM,2018);发现IL-25及IL-17A新受体IL-17RD调控银屑病的重要功能与机制（Immunity, 2018；Science Immunology, 2019); 发现IL-17D受体CD93及RORα-mTORc1轴并报道其在炎症性肠病中的重要功能（Immunity, 2021；Cell Reports, 2021);发现发烧促进Th17细胞分化并加重自身免疫病的重要功能与机制（Immunity, 2020)等等。除此之外，本项目还发现了若干调控生发中心T和B细胞发育及体液免疫应答的关键转录因子和信号通路（Immunity, 2019 & 2021; Cell Reports, 2021）。相关研究对于了解Th17细胞分化机制以及生发中心介导的体液免疫应答有重要帮助，并为自身免疫疾病的临床治疗提供了新的潜在药物靶点和重要线索。