FTO controls CD8⁺ T cell survival and effector response by modulating m⁶A 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 (m⁶A) 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 m⁶A 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 m⁶A reader insulin-like growth factor-2 mRNA-biding proteins 3 (IGF2BP3). Mutation of the Fas m⁶A 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 m⁶A 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.