N6-Methyladenosine Directly Regulates CD40L Expression In CD4+ T Lymphocytes

<p><strong>Abstract</strong></p> <p>T cell activation is a highly regulated process, modulated via the expression of various immune regulatory proteins including cytokines, surface receptors and co-stimulatory proteins. N⁶-methyladenosine (m⁶A) is an RNA modification that can directly regulate RNA expression levels and it is associated with various biological processes. However, the function of m⁶A in T cell activation remains incompletely understood. We identify m⁶A as a novel regulator of the expression of CD40 ligand (CD40L) in human CD4⁺ lymphocytes. Manipulation of the m⁶A &lsquo;eraser&rsquo; fat mass and obesity-associated protein (FTO) and m⁶A &lsquo;writer&rsquo; protein methyltransferase-like 3 (METTL3) directly affects the expression of CD40L. The m⁶A &lsquo;reader&rsquo; protein YT521-B homology domain family-2 (YTHDF2) is able to recognize and bind m⁶A specific sequences on the <em>CD40L</em> mRNA and promotes its degradation. This study demonstrates that CD40L expression in human primary CD4⁺ T lymphocytes is regulated via m⁶A modifications, elucidating a new regulatory mechanism in CD4⁺ T cell activation that could possibly be leveraged in the future to modulate T cell responses in patients with immune-related diseases.</p> <p>&nbsp;</p> <p><strong>Data deposited</strong></p> <ul> <li>meRIP sequencing: read counts&nbsp;of healthy control peripheral blood-derived CD4+ T lymphocytes (figure 1 in article).</li> <li>meRIP sequencing: per gene TMM normalized log2(CPM + 0.168) expression values of&nbsp;healthy control peripheral blood-derived CD4+ T lymphocytes (figure 1 in article). Also includes Log2FoldChange values or each gene.</li> </ul>