期刊
NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-21594-6
关键词
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资金
- National Key Research and Development Program of China [2017YFA0104401]
- National Natural Scientific Foundation of China [31970831, 31630038, 31571522, 31422037, 31825011, 31430022]
- State Key Laboratory of Agrobiotechnology of China Agricultural University [2018SKLAB6-30, 2019SKLAB6-6, 2019SKLAB6-7]
- Youth Innovation Promotion Association [CAS 2018133]
This study demonstrates the importance of RNA methylation in T-FH effector differentiation and subsequent antibody formation by stabilizing Tcf7 transcripts.
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.
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