2. Academic Validation
  3. Mettl3-m6A-Creb1 forms an intrinsic regulatory axis in maintaining iNKT cell pool and functional differentiation

Mettl3-m6A-Creb1 forms an intrinsic regulatory axis in maintaining iNKT cell pool and functional differentiation

  • Cell Rep. 2023 Jun 1;42(6):112584. doi: 10.1016/j.celrep.2023.112584.
Menghao You 1,  Jingjing Liu 1,  Jie Li 2,  Ce Ji 1,  Haochen Ni 3,  Wenhui Guo 1,  Jiarui Zhang 1,  Weiwei Jia 1,  Zhao Wang 1,  Yajiao Zhang 1,  Yingpeng Yao 1,  Guotao Yu 1,  Huanyu Ji 1,  Xiaohu Wang 4,  Dali Han 3,  Xuguang Du 5,  Meng Michelle Xu 6,  Shuyang Yu 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing 100193, China.
  • 2 Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, and China National Center for Bioinformation, Chinese Academy of Sciences, Beijing 100101, China; Department of Basic Medical Sciences, School of Medicine, Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, THU-PKU Center for Life Sciences, Tsinghua University, Beijing 100084, China.
  • 3 Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, and China National Center for Bioinformation, Chinese Academy of Sciences, Beijing 100101, China.
  • 4 Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China.
  • 5 State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing 100193, China. Electronic address: xuguangdu@cau.edu.cn.
  • 6 Department of Basic Medical Sciences, School of Medicine, Institute for Immunology, Beijing Key Lab for Immunological Research on Chronic Diseases, THU-PKU Center for Life Sciences, Tsinghua University, Beijing 100084, China. Electronic address: michellexu@mail.tsinghua.edu.cn.
  • 7 State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing 100193, China. Electronic address: ysy@cau.edu.cn.
PMID: 37267102 DOI: 10.1016/j.celrep.2023.112584
Abstract

N6-methyladenosine (m6A) methyltransferase METTL3 is involved in conventional T cell immunity; however, its role in innate immune cells remains largely unknown. Here, we show that METTL3 intrinsically regulates invariant natural killer T (iNKT) cell development and function in an m6A-dependent manner. Conditional ablation of METTL3 in CD4+CD8+ double-positive (DP) thymocytes impairs iNKT cell proliferation, differentiation, and cytokine secretion, which synergistically causes defects in B16F10 melanoma resistance. Transcriptomic and epi-transcriptomic analyses reveal that METTL3 deficiency disturbs the expression of iNKT cell-related genes with altered m6A modification. Strikingly, METTL3 modulates the stability of the Creb1 transcript, which in turn controls the protein and phosphorylation levels of Creb1. Furthermore, conditional targeting of Creb1 in DP thymocytes results in similar phenotypes of iNKT cells lacking METTL3. Importantly, ectopic expression of Creb1 largely rectifies such developmental defects in Mettl3-deficient iNKT cells. These findings reveal that the Mettl3-m6A-Creb1 axis plays critical roles in regulating iNKT cells at the post-transcriptional layer.

Keywords

CP: Immunology; Creb1; Mettl3; development; differentiation; iNKT; invariant natural killer T cell; m(6)A.

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