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
  • 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. [email protected].
  • 9. Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China. [email protected].
  • 10. Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China. [email protected].
  • 11. Xi'an Key Laboratory of Immune Related Diseases, Xi'an, Shannxi, China. [email protected].
  • 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. [email protected].
  • 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. [email protected].
  • 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. [email protected].
  • 15. Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, China. [email protected].
  • 16. Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China. [email protected].
  • 17. Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China. [email protected].
  • 18. Xi'an Key Laboratory of Immune Related Diseases, Xi'an, Shannxi, China. [email protected].
  • # 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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