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Transcription factor YY1 is essential for iNKT cell development

Cellular & Molecular Immunology volume 16, pages 547–556 (2019)Cite this article

Abstract

Invariant natural killer T (iNKT) cells develop from CD4+CD8+ double-positive (DP) thymocytes and express an invariant Vα14–Jα18 T-cell receptor (TCR) α-chain. Generation of these cells requires the prolonged survival of DP thymocytes to allow for Vα14–Jα18 gene rearrangements and strong TCR signaling to induce the expression of the iNKT lineage-specific transcription factor PLZF. Here, we report that the transcription factor Yin Yang 1 (YY1) is essential for iNKT cell formation. Thymocytes lacking YY1 displayed a block in iNKT cell development at the earliest progenitor stage. YY1-deficient thymocytes underwent normal Vα14–Jα18 gene rearrangements, but exhibited impaired cell survival. Deletion of the apoptotic protein BIM failed to rescue the defect in iNKT cell generation. Chromatin immunoprecipitation and deep-sequencing experiments demonstrated that YY1 directly binds and activates the promoter of the Plzf gene. Thus, YY1 plays essential roles in iNKT cell development by coordinately regulating cell survival and PLZF expression.

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Fig. 1: Lack of iNKT cells in Yy1f/fCd4Cre/+ (YY1-TKO) mice.
Fig. 2: YY1-TKO thymocytes manifest T-cell-intrinsic defect in iNKT cell development.
Fig. 3: Analysis of Vα14–Jα18 TCRα rearrangements in YY1-TKO thymocytes.
Fig. 4: Impaired thymocyte survival in YY1-TKO mice.
Fig. 5: BIM deletion fails to restore iNKT cell development in YY1-TKO mice.
Fig. 6: YY1 binds and transactivates the Plzf promoter.

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Acknowledgements

We thank Ms Lim Wei Lee for sample processing and plasmid construction. We also thank other members of the laboratory for insightful discussion and the A*STAR Biomedical Research Council for grant support.

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Authors and Affiliations

  1. Immunology Group, Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore, 138668, Singapore

    Xijun Ou, Jianxin Huo, Yuhan Huang, Yan-Feng Li, Shengli Xu & Kong-Peng Lam

  2. Department of Biology, Southern University of Science and Technology, Shenzhen, 518055, China

    Xijun Ou

  3. Department of Physiology, National University of Singapore, Singapore, 117599, Singapore

    Shengli Xu & Kong-Peng Lam

  4. Department of Microbiology and Immunology, National University of Singapore, Singapore, 117599, Singapore

    Kong-Peng Lam

  5. Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore

    Kong-Peng Lam

  6. School of Biological Sciences, Nanyang Technological University, Singapore, Singapore

    Kong-Peng Lam

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  1. Xijun Ou
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  2. Jianxin Huo
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  3. Yuhan Huang
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Contributions

X.O., S.X., and K.-P.L. designed the experiments and wrote the paper. X.O., J.H., Y.H., and Y.-F.L. conducted the experiments.

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Correspondence to Xijun Ou, Shengli Xu or Kong-Peng Lam.

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Ou, X., Huo, J., Huang, Y. et al. Transcription factor YY1 is essential for iNKT cell development. Cell Mol Immunol 16, 547–556 (2019). https://doi.org/10.1038/s41423-018-0002-6

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