2. Academic Validation
  3. FTO controls CD8+ T cell survival and effector response by modulating m6A methylation of Fas

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

  • Cell Death Dis. 2025 Apr 15;16(1):301. doi: 10.1038/s41419-025-07606-z.
Lina Sun # 1 2 3 4,  Tianzhe Zhang # 1 2 3 4,  Yao Ge # 5,  Zhihong Yao # 1 6,  Yanhong Su # 1 2 3 4,  Qianhao Wang 1 2 3 4,  Yang Chen 5,  Boxiao He 1 2,  Renyi Ding 1 2,  Cangang Zhang 1 2,  Linbo Lan 7,  Ruonan Liu 1 2,  Huanxin Ping 1 2,  Dan Zhang 1 2,  Lin Shi 1 2 4,  Xiaobo Zhou 1 2 4,  Xiaoxuan Jia 2,  Chenming Sun 8 9 10 11,  Lingli Liang 12,  Lianjun Zhang 13 14,  Baojun Zhang 15 16 17 18
Affiliations

Affiliations

  • 1 Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
  • 2 Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.
  • 3 Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China.
  • 4 Xi'an Key Laboratory of Immune Related Diseases, Xi'an, Shannxi, China.
  • 5 Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
  • 6 Faculty of Clinical Medicine, Hanzhong Vocational and Technical College, Hanzhong, China.
  • 7 Clinical Teaching and Research Center, School of Nursing, Weinan Vocational and Technical College, Weinan, Shaanxi, China.
  • 8 Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, China. cm.sun@xjtu.edu.cn.
  • 9 Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China. cm.sun@xjtu.edu.cn.
  • 10 Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China. cm.sun@xjtu.edu.cn.
  • 11 Xi'an Key Laboratory of Immune Related Diseases, Xi'an, Shannxi, China. cm.sun@xjtu.edu.cn.
  • 12 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, PR China; Institute of Neuroscience, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, PR China. ll2017@xjtu.edu.cn.
  • 13 National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu, China. zlj@ism.cams.cn.
  • 14 Key Laboratory of Synthetic Biology Regulatory Elements, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, 215123, Jiangsu, China. zlj@ism.cams.cn.
  • 15 Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, China. bj.zhang@mail.xjtu.edu.cn.
  • 16 Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China. bj.zhang@mail.xjtu.edu.cn.
  • 17 Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China. bj.zhang@mail.xjtu.edu.cn.
  • 18 Xi'an Key Laboratory of Immune Related Diseases, Xi'an, Shannxi, China. bj.zhang@mail.xjtu.edu.cn.
  • # Contributed equally.
PMID: 40234389 DOI: 10.1038/s41419-025-07606-z
Abstract

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.

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