M6a dot blot protocol12/2/2023 In the LZ, where positive and negative selection take place, affinity maturation of Ag-specific BCRs occurs through competition for Ags displayed on the surface of follicular dendritic cells and for the help from the limited number of T follicular helper cells ( 5, 6). In the DZ, B cells undergo robust proliferation and somatic hypermutation of their Ig V region genes catalyzed by activation-induced cytidine deaminase (AID, encoded by Aicda) ( 4). GCs comprise two anatomically and functionally distinct zones, that is, the dark zone (DZ) and light zone (LZ) ( 3). Most long-lived PCs and memory B cells are generated in response to protein Ags in germinal centers (GCs), which are temporary microstructures in the peripheral lymphoid organs such as the spleen and lymph nodes ( 2). Upon engagement by foreign Ags, resting B cells undergo extensive proliferation and differentiate into long-lived Ab-secreting plasma cells (PCs) and memory B cells, providing an individual with lifelong protective humoral immunity ( 1). Thus, our findings suggest that Mettl14-mediated m6A modification plays an essential role in the GC B cell response. 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. 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. Ablation of Mettl14 in B cells leads to compromised GC B cell proliferation and a defective Ab response. In this study, we show that methyltransferase like 14 (Mettl14)–mediated methylation of adenosines at the position N 6 of mRNA ( N 6-methyladenosine ) is essential for the GC B cell response in mice. 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 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. 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.
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