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<p>Functional CD8<sup>+</sup> T cell immunity is essential for immune surveillance and host defense against infection and tumors. Epigenetic mechanisms, particularly RNA modification, in controlling CD8<sup>+</sup> 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 (m<sup>6</sup>A) demethylase, we revealed that FTO was indispensable for adequate CD8<sup>+</sup> T cell immune response and protective function. FTO ablation led to considerable cell death in activated CD8<sup>+</sup> T cells, which was attributed to cell apoptosis. MeRIP-seq analysis revealed an increase in m<sup>6</sup>A methylation on <i>Fas</i> mRNA in FTO-deficient CD8<sup>+</sup> T cells. The loss of FTO promoted Fas expression via enhancing the <i>Fas</i> mRNA stability, which depended on the m<sup>6</sup>A reader insulin-like growth factor-2 mRNA-biding proteins 3 (IGF2BP3). Mutation of the <i>Fas</i> m<sup>6</sup>A sites or knockdown IGF2BP3 could normalize the upregulated Fas expression and apoptosis levels caused by FTO ablation in CD8<sup>+</sup> T cells. Our findings delineate a novel epigenetic regulatory mechanism of FTO-mediated m<sup>6</sup>A modification in supporting CD8<sup>+</sup> T cell survival and effector responses, providing new insights into understanding the post-transcriptional regulation in CD8<sup>+</sup> T cell immunological functions and the potential therapeutic intervention.</p>

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FTO controls CD8+ T cell survival and effector response by modulating m6A methylation of Fas

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月15日

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  • Lina Sun,
  • Tianzhe Zhang,
  • Yao Ge,
  • Zhihong Yao,
  • Yanhong Su,
  • Qianhao Wang,
  • Yang Chen,
  • Boxiao He,
  • Renyi Ding,
  • Cangang Zhang,
  • Linbo Lan,
  • Ruonan Liu,
  • Huanxin Ping,
  • Dan Zhang,
  • Lin Shi,
  • Xiaobo Zhou,
  • Xiaoxuan Jia,
  • Chenming Sun,
  • Lingli Liang,
  • Lianjun Zhang,
  • Baojun Zhang

摘要

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.