METTL3-dependent m6A modification programs T follicular helper cell differentiation

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. T follicular helper (T-FH) cells are specialized effector CD4(+) T cells that are critical in humoral immunity, but the function of post-transcriptional regulation is not clearly defined. Here, the authors demonstrate that RNA methylation is important for T-FH effector differentiation and subsequent antibody formation through stabilization of Tcf7 transcripts.

Automated summary

This study demonstrates the importance of RNA methylation in T-FH effector differentiation and subsequent antibody formation by stabilizing Tcf7 transcripts.