m6A mRNA甲基化修饰调控γδT17细胞分化和功能研究

γδT17 cells, as a functional subset of γδT cells, play a regulatory role in various diseases. Our published results indicate that mTORC1 and mTORC2 synergistically promote γδT17 cell differentiation through different metabolic mechanisms, thereby aggravate the degree of psoriasis in mice, but the upstream regulatory mechanism of mTOR signaling remains unknown. Mettl3-mediated m6A mRNA methylation modification can regulate cell proliferation, differentiation and function. Previous studies show that Mettl3 significantly promote the differentiation of γδT17 cells and their activation of mTOR signaling. We therefore propose the hypothesis that Mettl3 promotes γδT17 cell differentiation by activating mTOR-mediated metabolic pathways. The key scientific questions to be solved are: ① Whether Mettl3 promoting the differentiation of γδT17 cells could promote the psoriasis process in mice? ② What is the mechanism of Mettl3 promoting the differentiation of γδT17 cells? ③ Does Mettl3 promote the differentiation of γδT17 cells in clinical samples? This study will help clarify the mechanism by which Mettl3 regulates the differentiation of γδT17 cells and then affects the process of psoriasis, and provides a theoretical basis for γδT cells as targets for treatment of chronic inflammatory disease.

γδT17细胞作为γδT细胞的一个功能亚群，在多种疾病中发挥调控作用。申请人已发表结果表明，mTORC1和mTORC2通过不同的代谢机制协同促进γδT17细胞分化，进而加重小鼠银屑病程度，但mTOR信号上游调控机制仍未知。Mettl3介导的m6A mRNA甲基化修饰能够调控细胞增殖、分化及功能。预实验结果发现Mettl3显著促进γδT17细胞分化及其mTOR信号活化。因此我们提出假设：Mettl3通过激活mTOR信号介导的代谢途径促进γδT17细胞分化。拟解决的关键科学问题是：①Mettl3促进γδT17细胞分化是否能促进小鼠的银屑病进程？②Mettl3促进γδT17细胞分化的具体机制是什么？③Mettl3促进γδT17细胞分化的机制是否适用于临床样本？该研究将阐明Mettl3调控γδT17细胞分化进而影响银屑病进程的机制，为γδT细胞作为慢性炎症性疾病干预靶点提供理论基础。

γδT细胞通过两个主要功能不同的子集γδT1和γδT17对组织生理学和免疫监视做出重要贡献。m6A甲基化在控制mRNA代谢的许多方面起着关键作用，这些方面控制着mRNA转换、基因表达和细胞功能特化，但是，它在gdT细胞中的作用尚不清楚。在这里，我们发现m6A甲基化控制着γδT17与gdT1细胞的功能规范。从机制上讲，m6A甲基化可防止内源性双链RNA的形成并促进Stat1转录物的降解，这些转录物会聚以防止STAT1信号的过度激活和随后促进γδT1但抑制γδT17分化。在γδT细胞中删除m6A甲基转移酶复合物中的关键酶Mettl3可减少IL-17的产生并改善小鼠的γδT17介导的银屑病。总之，我们的研究结果表明，m6A甲基化协调mRNA稳定性和dsRNA含量以平衡γδT1和γδT17细胞。另外，我们还绘制了小鼠主要免疫器官的单细胞转录图谱和单细胞染色质可及性图谱，为γδT细胞的研究提供了宝贵的资源库，并发现了重要的调控γδT17分化的转录因子Nr1d1。同时，我们还发现了γδT1细胞在小鼠肝纤维化模型中的重要保护性作用，为基于γδT细胞的免疫治疗提供了重要的理论基础。