METTL3-dependent m6A modification programs T follicular helper cell differentiation

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 N⁶-methyladenosine (m⁶A) 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. m⁶A-miCLIP-seq shows the 3' UTR of Tcf7 mRNA is subjected to METTL3-dependent m⁶A modification. Loss of METTL3 or mutation of the Tcf7 3' UTR m⁶A 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 m⁶A modification to ensure activation of a T_FH transcriptional program, indicating a pivotal function of post-transcriptional regulation in promoting T_FH cell differentiation.