The m6A demethylase FTO controls activation-induced cell death in effector CD8+ T cells by modulating Fas expression

Functional CD8+ T cell immune response is critical for immune surveillance and host defense against infection and tumor. Epigenetic mechanisms associated with RNA modification in controlling CD8+ T cell response remain poorly understood. 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 sufficient CD8+ T cell immune response and protective function. FTO ablation led to considerable cell death in activated CD8+ T cells, which was attributed to apoptosis. MeRIP-seq analysis identified the upregulated m6A modification on Fas mRNA in FTO deficient CD8+ T cells. Loss of FTO promoted Fas expression via enhancing the Fas mRNA stability dependent on m6A reader IGF2BP3. Mutation of the Fas m6A sites or knockdown IGF2BP3 could rescue the upregulated Fas expression and cell apoptosis caused by FTO ablation in CD8+ T cells. Our findings defined a novel epigenetic regulatory mechanism of FTO-mediated m6A modification in supporting CD8+ T cell immune responses, providing new insights into understanding the post-transcriptional regulation in CD8+ T cell immunological functions. Overall design: WT and FTO KO CD8+ T cells (OT-1+) transferred into recipient mice before infection with LM-OVA for 5 days. WT and FTO KO CD8+ T cells (OT-1+) transferred into recipient mice before infection with LM-OVA for 5 days. WT and KO CD8+ T cells were isolated for RNA-seq and MeRIP-seq. m6A immunoprecipitation and sequencing were performed at the LC Sciences, LLC on an Illumina Novaseq™ 6000 platform with 2×150bp paired-end sequencing (PE150).