METTL3-mediated m6A methylation orchestrates mRNA stability and dsRNA contents to equilibrate γδ T1 and γδ T17 cells

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. [Display omitted] •METTL3-mediated m6A mRNA modification promotes γδ T17 but inhibits γδ T1 differentiation•m6A modification accelerates the degradation of Stat1 transcripts•m6A modification prevents aberrant production of endogenous dsRNA•METTL3-deficient γδ T cells are less pathogenic in driving psoriasis Xiao et al. show that METTL3-mediated m6A modification has a significant impact on the formation of endogenous dsRNA and the degradation of targeted transcripts in γδ T cells and therefore affects their differentiation. METTL3-deficient γδ T cells produce less IL-17 and are less pathogenic in driving psoriatic skin inflammation.