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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.

METTL3-dependent m6A modification programs T follicular helper cell differentiation