https://orcid.org/0000-0001-9842-9312
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Hengjun Huang, Gaopu Zhang, Gui-Xin Ruan, Yuxing Li, Wenjing Chen, Jia Zou, Rui Zhang, Jing Wang, Sheng-Jian Ji, Shengli Xu, Xijun Ou, Mettl14-Mediated m6A Modification Is Essential for Germinal Center B Cell Response, The Journal of Immunology, Volume 208, Issue 8, April 2022, Pages 1924–1936, https://doi.org/10.4049/jimmunol.2101071
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Abstract
The germinal center (GC) response is essential for generating memory B and long-lived Ab-secreting plasma cells during the T cell–dependent immune response. In the GC, signals via the BCR and CD40 collaboratively promote the proliferation and positive selection of GC B cells expressing BCRs with high affinities for specific Ags. Although a complex gene transcriptional regulatory network is known to control the GC response, it remains elusive how the positive selection of GC B cells is modulated posttranscriptionally. In this study, we show that methyltransferase like 14 (Mettl14)–mediated methylation of adenosines at the position N6 of mRNA (N6-methyladenosine [m6A]) is essential for the GC B cell response in mice. Ablation of Mettl14 in B cells leads to compromised GC B cell proliferation and a defective Ab response. Interestingly, we unravel that Mettl14-mediated m6A regulates the expression of genes critical for positive selection and cell cycle regulation of GC B cells in a Ythdf2-dependent but Myc-independent manner. Furthermore, our study reveals that Mettl14-mediated m6A modification promotes mRNA decay of negative immune regulators, such as Lax1 and Tipe2, to upregulate genes requisite for GC B cell positive selection and proliferation. Thus, our findings suggest that Mettl14-mediated m6A modification plays an essential role in the GC B cell response.
