Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai 519000, China; The Biomedical Translational Research Institute, Key Laboratory of Ministry of Education for Viral Pathogenesis & Infection Prevention and Control, Health Science Center (School of Medicine), Jinan University, Guangzhou 510632, China.
National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518172, China.
Cell Rep. 2023 Jul 25;42(7):112684. doi: 10.1016/j.celrep.2023.112684. Epub 2023 Jun 23.
γδ T cells make key contributions to tissue physiology and immunosurveillance through two main functionally distinct subsets, γδ T1 and γδ T17. m6A methylation plays critical roles in controlling numerous aspects of mRNA metabolism that govern mRNA turnover, gene expression, and cellular functional specialization; however, its role in γδ T cells remains less well understood. Here, we find that m6A methylation controls the functional specification of γδ T17 vs. γδ T1 cells. Mechanistically, m6A methylation prevents the formation of endogenous double-stranded RNAs and promotes the degradation of Stat1 transcripts, which converge to prevent over-activation of STAT1 signaling and ensuing inhibition of γδ T17. Deleting Mettl3, the key enzyme in the m6A methyltransferases complex, in γδ T cells reduces interleukin-17 (IL-17) production and ameliorates γδ T17-mediated psoriasis. In summary, our work shows that METTL3-mediated m6A methylation orchestrates mRNA stability and double-stranded RNA (dsRNA) contents to equilibrate γδ T1 and γδ T17 cells.
γδ T 细胞通过两个主要功能不同的亚群（γδ T1 和 γδ T17）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 代谢的许多方面发挥着关键作用，这些方面控制着 mRNA 周转、基因表达和细胞功能特化；然而，其在 γδ T 细胞中的作用仍不太清楚。在这里，我们发现 m6A 甲基化控制着 γδ T17 与 γδ T1 细胞的功能特化。在机制上，m6A 甲基化阻止了内源性双链 RNA 的形成，并促进了 Stat1 转录本的降解，这两者共同作用防止了 STAT1 信号的过度激活，并抑制了 γδ T17。在 γδ T 细胞中删除 m6A 甲基转移酶复合物的关键酶 Mettl3，会减少白细胞介素 17（IL-17）的产生，并改善 γδ T17 介导的银屑病。总之，我们的工作表明，METTL3 介导的 m6A 甲基化协调 mRNA 稳定性和双链 RNA（dsRNA）含量，以平衡 γδ T1 和 γδ T17 细胞。
