Mettl14-Mediated m6A Modification Is Essential for Germinal Center B Cell Response

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.

m6A regulation of cortical and retinal neurogenesis is mediated by the redundant m6A readers YTHDFs

“…Mettl14 fl/fl , Ythdf1 fl/fl and Ythdf2 fl/fl mice were reported previously ( Huang et al., 2022 ; Yu et al., 2021 ; Zhuang et al., 2019 ). For generation of Ythdf3 conditional knockout mice, exon 3 of mouse Ythdf3 was targeted and loxP sites were inserted flanking Ythdf3 exon 3.…”

Aberrant RNA m6A modification in gastrointestinal malignancies: versatile regulators of cancer hallmarks and novel therapeutic opportunities

“…On another note, while studies are lacking assessing m 6 A regulated B cell dysregulation in TIME, B cells in the germinal center of a non-tumor model, are tightly controlled by METTL3 and METTL14, indicating their potential application in potential B cell targeted immunotherapy in the future [ 137 , 138 ].…”

“…Similarily, after confirmation of IGF2BP1 as a crucial regulator of T cell composition in the TIME of HCC, an IGF2BP1 small molecule inhibitor exhibited the ability to recruit not only CD4 + and CD8 + T cells, but also CD56 + NK cells and F4/80 + macrophage, into the TIME [136]. On another note, while studies are lacking assessing m 6 A regulated B cell dysregulation in TIME, B cells in the germinal center of a non-tumor model, are tightly controlled by METTL3 and METTL14, indicating their potential application in potential B cell targeted immunotherapy in the future [137,138].…”

The RNA-binding protein hnRNP F is required for the germinal center B cell response

“…ELISA NP-specific antibodies levels were detected using ELISA as described previously 56 . Briefly, sera were collected before and after NP-CGG immunization on the indicated days.…”