Abstract
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.
Highlights
T follicular helper (TFH) cells are specialized effector CD4+ T cells critical to humoral immunity
The frequency and numbers of CD44+CXCR5+ TFH cells were significantly diminished in Mettl3fl/flCd4-Cre mice compared with those in their control littermates on day 8 post viral infection (Fig. 1a, b)
These results indicated that METTL3 deficiency severely impairs TFH differentiation
Summary
T follicular helper (TFH) cells are specialized effector CD4+ T cells critical to humoral immunity. METTL3 is necessary for expression of important TFH signature genes, including Tcf[7], Bcl[6], Icos and Cxcr[5] and these effects depend on intact methyltransferase activity. Our findings indicate that METTL3 stabilizes Tcf[7] 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. As a master regulator of TFH differentiation, Bcl-6 represses the TH1, TH2, and TH17 lineage-specific transcription factors to promote the differentiation of activated CD4+ T cells into TFH cells[7,8,9]. In the context of viral infection, m6A represses type I interferon production in an innate antiviral state[27,28] Despite these profound effects of m6A modification on immunoregulation, its role in TFH differentiation has not been determined
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