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关键贡献。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，它在 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 γδ T17 与 γδ T1 细胞的功能规范。从机制上讲，m6A 甲基化可防止内源双链 RNA 的形成并促进Stat1转录本的降解，这些转录本会聚合以防止 STAT1 信号传导过度激活并随后抑制 γδ T17。删除γδ T 细胞中 m6A 甲基转移酶复合物中的关键酶 Mettl3 可减少白细胞介素 17 (IL-17) 的产生并改善 γδ T17 介导的牛皮癣。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。