FTO controls CD8 T cell survival and effector response by modulating mA methylation of Fas.

Functional CD8 T cell immunity is essential for immune surveillance and host defense against infection and tumors. Epigenetic mechanisms, particularly RNA modification, in controlling CD8 T cell immune response is not fully elucidated. Here, by T cell-specific deletion of fat mass and obesity-associated protein (FTO), a critical N6-methyladenosine (mA) demethylase, we revealed that FTO was indispensable for adequate CD8 T cell immune response and protective function. FTO ablation led to considerable cell death in activated CD8 T cells, which was attributed to cell apoptosis. MeRIP-seq analysis revealed an increase in mA methylation on Fas mRNA in FTO-deficient CD8 T cells. The loss of FTO promoted Fas expression via enhancing the Fas mRNA stability, which depended on the mA reader insulin-like growth factor-2 mRNA-biding proteins 3 (IGF2BP3). Mutation of the Fas mA sites or knockdown IGF2BP3 could normalize the upregulated Fas expression and apoptosis levels caused by FTO ablation in CD8 T cells. Our findings delineate a novel epigenetic regulatory mechanism of FTO-mediated mA modification in supporting CD8 T cell survival and effector responses, providing new insights into understanding the post-transcriptional regulation in CD8 T cell immunological functions and the potential therapeutic intervention.