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Cellular & molecular immunology
11, 2021;18 (11): 2502-2515.

SRSF1 plays a critical role in invariant natural killer T cell development and function.

Jingjing Liu, Menghao You, Yingpeng Yao, Ce Ji, Zhao Wang, Fang Wang, Di Wang, Zhihong Qi, Guotao Yu, Zhen Sun, Wenhui Guo, Juanjuan Liu, Shumin Li, Yipeng Jin, Tianyan Zhao, Hai-Hui Xue, Yuanchao Xue, Shuyang Yu
Author Information
  1. Jingjing Liu: State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China. ORCID
  2. Menghao You: State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.
  3. Yingpeng Yao: State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China. ORCID
  4. Ce Ji: State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.
  5. Zhao Wang: State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.
  6. Fang Wang: State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.
  7. Di Wang: Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
  8. Zhihong Qi: State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.
  9. Guotao Yu: State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.
  10. Zhen Sun: State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.
  11. Wenhui Guo: State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.
  12. Juanjuan Liu: State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.
  13. Shumin Li: Clinical Department, College of Veterinary Medicine, China Agricultural University, Beijing, China.
  14. Yipeng Jin: Clinical Department, College of Veterinary Medicine, China Agricultural University, Beijing, China.
  15. Tianyan Zhao: State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.
  16. Hai-Hui Xue: Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, USA. ORCID
  17. Yuanchao Xue: Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
  18. Shuyang Yu: State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China. ysy@cau.edu.cn. ORCID
PMID: 34522020 DOI: 10.1038/s41423-021-00766-w

Abstract

Invariant natural killer T (iNKT) cells are highly conserved innate-like T lymphocytes that originate from CD4CD8 double-positive (DP) thymocytes. Here, we report that serine/arginine splicing factor 1 (SRSF1) intrinsically regulates iNKT cell development by directly targeting Myb and balancing the abundance of short and long isoforms. Conditional ablation of SRSF1 in DP cells led to a substantially diminished iNKT cell pool due to defects in proliferation, survival, and TCRα rearrangement. The transition from stage 0 to stage 1 of iNKT cells was substantially blocked, and the iNKT2 subset was notably diminished in SRSF1-deficient mice. SRSF1 deficiency resulted in aberrant expression of a series of regulators that are tightly correlated with iNKT cell development and iNKT2 differentiation, including Myb, PLZF, Gata3, ICOS, and CD5. In particular, we found that SRSF1 directly binds and regulates pre-mRNA alternative splicing of Myb and that the expression of the short isoform of Myb is substantially reduced in SRSF1-deficient DP and iNKT cells. Strikingly, ectopic expression of the Myb short isoform partially rectified the defects caused by ablation of SRSF1. Furthermore, we confirmed that the SRSF1-deficient mice exhibited resistance to acute liver injury upon α-GalCer and Con A induction. Our findings thus uncovered a previously unknown role of SRSF1 as an essential post-transcriptional regulator in iNKT cell development and functional differentiation, providing new clinical insights into iNKT-correlated disease.

Keywords

Alternative splicing Development Function Invariant natural killer T cell SRSF1

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Grants

  1. 32130039/National Natural Science Foundation of China (National Science Foundation of China)
  2. 31970831/National Natural Science Foundation of China (National Science Foundation of China)
  3. 31630038/National Natural Science Foundation of China (National Science Foundation of China)

MeSH Term

Animals
Cell Differentiation
Cell Proliferation
Cells, Cultured
Chemical and Drug Induced Liver Injury
Clonal Selection, Antigen-Mediated
Cytotoxicity, Immunologic
Immunity, Innate
Lymphocyte Activation
Mice
Mice, Inbred C57BL
Mice, Knockout
Natural Killer T-Cells
Proto-Oncogene Proteins c-myb
Serine-Arginine Splicing Factors

Chemicals

Proto-Oncogene Proteins c-myb
Srsf1 protein, mouse
Serine-Arginine Splicing Factors
Journal Article Research Support, Non-U.S. Gov't
Article has an altmetric score of 1

Word Cloud

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