METTL3-dependent m6A modification programs T follicular helper cell differentiation

Abstract

Abstract T follicular helper (T FH ) cells are specialized effector CD4 + T cells critical to humoral immunity. Whether post-transcriptional regulation has a function in T FH cells is unknown. Here, we show conditional deletion of METTL3 (a methyltransferase catalyzing mRNA N 6 -methyladenosine (m 6 A) modification) in CD4 + T cells impairs T FH differentiation and germinal center responses in a cell-intrinsic manner in mice. METTL3 is necessary for expression of important T FH signature genes, including Tcf7 , Bcl6 , Icos and Cxcr5 and these effects depend on intact methyltransferase activity. m 6 A-miCLIP-seq shows the 3′ UTR of Tcf7 mRNA is subjected to METTL3-dependent m 6 A modification. Loss of METTL3 or mutation of the Tcf7 3′ UTR m 6 A site results in accelerated decay of Tcf7 transcripts. Importantly, ectopic expression of TCF-1 (encoded by Tcf7 ) rectifies T FH defects owing to METTL3 deficiency. Our findings indicate that METTL3 stabilizes Tcf7 transcripts via m 6 A modification to ensure activation of a T FH transcriptional program, indicating a pivotal function of post-transcriptional regulation in promoting T FH cell differentiation.