METTL3-dependent m6A modification programs T follicular helper cell differentiation

• Published in: Nature communications Vol. 12; no. 1; pp. 1333 - 16
• Main Authors: Yao, Yingpeng, Yang, Ying, Guo, Wenhui, Xu, Lifan, You, Menghao, Zhang, Yi-Chang, Sun, Zhen, Cui, Xiao, Yu, Guotao, Qi, Zhihong, Liu, Jingjing, Wang, Fang, Liu, Juanjuan, Zhao, Tianyan, Ye, Lilin, Yang, Yun-Gui, Yu, Shuyang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.02.2021; Nature Portfolio
• Subjects: 13/1; 13/109; 13/31; 13/44; 14/19; 38; 38/70; 38/88; 38/90; 38/91; 631/250/1619/554/1898/1270; 631/250/2152/1566/2493; Humanities and Social Sciences; multidisciplinary; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-21594-6

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.