Abstract：
Efficient immune responses rely on the proper differentiation of CD8+ T cells into effector and memory cells. Here, we show a critical requirement of N6-Methyladenosine (m6A) methyltransferase Mettl3 during CD8+ T cell responses upon acute viral infection. Conditional deletion of Mettl3 in CD8+ T cells impairs effector expansion and terminal differentiation in an m6A-dependent manner, subsequently affecting memory formation and the secondary response of CD8+ T cells. Our combined RNA-seq and m6A-miCLIP-seq analyses reveal that Mettl3 deficiency broadly impacts the expression of cell cycle and transcriptional regulators. Remarkably, Mettl3 binds to the Tbx21 transcript and stabilizes it, promoting effector differentiation of CD8+ T cells. Moreover, ectopic expression of T-bet partially restores the defects in CD8+ T cell differentiation in the absence of Mettl3. Thus, our study highlights the role of Mettl3 in regulating multiple target genes in an m6A-dependent manner and underscores the importance of m6A modification during CD8+ T cell response.
摘要：
有效的免疫应答依赖于CD8+T细胞正确分化为效应细胞和记忆细胞。这里,我们显示了急性病毒感染时CD8+T细胞应答期间N6-甲基腺苷（m6A）甲基转移酶Mettl3的关键需求。CD8+T细胞中Mettl3的条件缺失以m6A依赖性方式损害效应子扩增和终末分化，随后影响记忆形成和CD8+T细胞的次级反应。我们的组合RNA-seq和m6A-miCLIP-seq分析显示Mettl3缺陷广泛影响细胞周期和转录调节因子的表达。值得注意的是,Mettl3与Tbx21转录物结合并使其稳定，促进CD8+T细胞的效应子分化。此外，在没有Mettl3的情况下，T-bet的异位表达部分恢复了CD8+T细胞分化的缺陷。因此，我们的研究强调了Mettl3在以m6A依赖性方式调节多个靶基因中的作用,并强调了在CD8+T细胞应答过程中m6A修饰的重要性.
