Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, 320 E. Superior Street, Searle 3-401, Chicago, IL 60611, USA.
Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Cell Rep. 2022 Aug 2;40(5):111156. doi: 10.1016/j.celrep.2022.111156.
N-methyladenosine (mA), the most common form of RNA modification, controls CD4 T cell homeostasis by targeting the IL-7/STAT5/SOCS signaling pathways. The role of mA modification in unconventional T cell development remains unknown. Using mice with T cell-specific deletion of RNA methyltransferase METTL14 (T-Mettl14), we demonstrate that mA modification is indispensable for iNKT cell homeostasis. Loss of METTL14-dependent mA modification leads to the upregulation of apoptosis in double-positive thymocytes, which in turn decreases Vα14-Jα18 gene rearrangements, resulting in drastic reduction of iNKT numbers in the thymus and periphery. Residual T-Mettl14 iNKT cells exhibit increased apoptosis, impaired maturation, and decreased responsiveness to IL-2/IL-15 and TCR stimulation. Furthermore, METTL14 knockdown in mature iNKT cells diminishes their cytokine production, correlating with increased Cish expression and decreased TCR signaling. Collectively, our study highlights a critical role for METTL14-dependent-mA modification in iNKT cell development and function.
N6-甲基腺苷（m6A）是 RNA 修饰中最常见的形式，通过靶向 IL-7/STAT5/SOCS 信号通路来控制 CD4 T 细胞的动态平衡。m6A 修饰在非常规 T 细胞发育中的作用尚不清楚。我们利用 T 细胞特异性敲除 RNA 甲基转移酶 METTL14（T-Mettl14）的小鼠，证明了 m6A 修饰对于 iNKT 细胞的动态平衡是必不可少的。丧失 METTL14 依赖性 m6A 修饰会导致双阳性胸腺细胞中的细胞凋亡上调，进而减少 Vα14-Jα18 基因重排，导致胸腺和外周血中 iNKT 细胞数量急剧减少。残留的 T-Mettl14 iNKT 细胞表现出凋亡增加、成熟受损以及对 IL-2/IL-15 和 TCR 刺激的反应性降低。此外，成熟 iNKT 细胞中 METTL14 的敲低会降低其细胞因子的产生，这与 Cish 表达增加和 TCR 信号转导降低有关。总之，我们的研究强调了 METTL14 依赖性 m6A 修饰在 iNKT 细胞发育和功能中的关键作用。
