METTL3-dependent m6A modification programs T follicular helper cell differentiation

Nat Commun. 2021 Feb 26;12(1):1333. doi: 10.1038/s41467-021-21594-6.


T follicular helper (TFH) cells are specialized effector CD4+ T cells critical to humoral immunity. Whether post-transcriptional regulation has a function in TFH cells is unknown. Here, we show conditional deletion of METTL3 (a methyltransferase catalyzing mRNA N6-methyladenosine (m6A) modification) in CD4+ T cells impairs TFH differentiation and germinal center responses in a cell-intrinsic manner in mice. METTL3 is necessary for expression of important TFH 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 TFH defects owing to METTL3 deficiency. Our findings indicate that METTL3 stabilizes Tcf7 transcripts via m6A modification to ensure activation of a TFH transcriptional program, indicating a pivotal function of post-transcriptional regulation in promoting TFH cell differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / genetics*
  • Cell Differentiation / physiology*
  • Gene Expression Regulation
  • Gene Knockdown Techniques
  • Germinal Center / immunology
  • Hepatocyte Nuclear Factor 1-alpha / metabolism
  • Lymphocyte Activation
  • Lymphocytes, Null
  • Methyltransferases / genetics*
  • Methyltransferases / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Proto-Oncogene Proteins c-bcl-6 / metabolism
  • RNA, Messenger / metabolism
  • Receptors, CXCR5 / metabolism
  • T Follicular Helper Cells / metabolism*


  • Bcl6 protein, mouse
  • CXCR5 protein, mouse
  • Hepatocyte Nuclear Factor 1-alpha
  • Hnf1a protein, mouse
  • Proto-Oncogene Proteins c-bcl-6
  • RNA, Messenger
  • Receptors, CXCR5
  • Methyltransferases
  • Mettl3 protein, mouse