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

Abstract

Invariant natural killer T (iNKT) cells are highly conserved innate-like T lymphocytes that originate from CD4+CD8+ 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.

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Acknowledgements

This work was supported in part by grants from the National Key Research and Development Program of China (2017YFA0104401), the National Natural Scientific Foundation of China (32130039, 31970831, and 31630038), and the Project for Extramural Scientists of State Key Laboratory of Agrobiotechnology from China Agricultural University (2021SKLAB6-3, 2021SKLAB6-4, 2019SKLAB6-6, and 2019SKLAB6-7).

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Contributions

Jingjing L., M.Y., and C.J. performed the major experiments and analyzed the data; M.Y., Z.W., and F.W. analyzed the high-throughput data; D.W., Z.Q., Y.Y., G.Y., Z.S., W.G., Juanjuan L., S.L., Y.J., and T.Z. assisted with the overall experiments; S.Y. designed and supervised the experiments with constructive suggestions from H.-H.X. and Y.X.; Y.Y., Jingjing L., and S.Y. wrote the manuscript with revisions from all authors.

Corresponding author

Correspondence to Shuyang Yu.

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The authors declare no competing interests.

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Liu, J., You, M., Yao, Y. et al. SRSF1 plays a critical role in invariant natural killer T cell development and function. Cell Mol Immunol 18, 2502–2515 (2021). https://doi.org/10.1038/s41423-021-00766-w

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Keywords

  • Invariant natural killer T cell
  • SRSF1
  • Development
  • Function
  • Alternative splicing

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