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Ssu72 is a T-cell receptor-responsive modifier that is indispensable for regulatory T cells

Cellular & Molecular Immunology volume 18, pages 1395–1411 (2021)Cite this article

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Abstract

The homeostatic balance between effector T cells and regulatory T cells (Tregs) is crucial for adaptive immunity; however, epigenetic programs that inhibit phosphorylation to regulate Treg development, peripheral expression, and suppressive activity are elusive. Here, we found that the Ssu72 phosphatase is activated by various T-cell receptor signaling pathways, including the T-cell receptor and IL-2R pathways, and localizes at the cell membrane. Deletion of Ssu72 in T cells disrupts CD4+ T-cell differentiation into Tregs in the periphery via the production of high levels of the effector cytokines IL-2 and IFNγ, which induce CD4+ T-cell activation and differentiation into effector cell lineages. We also found a close correlation between downregulation of Ssu72 and severe defects in mucosal tolerance in patients. Interestingly, Ssu72 forms a complex with PLCγ1, which is an essential effector molecule for T-cell receptor signaling as well as Treg development and function. Ssu72 deficiency impairs PLCγ1 downstream signaling and results in failure of Foxp3 induction. Thus, our studies show that the Ssu72-mediated cytokine response coordinates the differentiation and function of Treg cells in the periphery.

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Acknowledgements

This study was supported by a National Research Foundation grant funded by the Korean government (MEST) (2017R1A2B3006776).

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  1. These authors contributed equally: Jin-Kwan Lee, Seo-Young Koo

Authors and Affiliations

  1. Research Institute, Curogen Technology, Suwon, South Korea

    Jin-Kwan Lee & Chang-Woo Lee

  2. Department of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Suwon, South Korea

    Seo-Young Koo, Hye-Mi Nam, Jee-Boong Lee, Kyung-Mo Kim, Eun-Ji Park & Chang-Woo Lee

  3. MOGAM Institute for Biomedical Research, Gyeonggi, South Korea

    Hye-Mi Nam

  4. Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea

    Jiwon Ko

  5. Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea

    Jiwon Ko & Heounjeong Go

  6. Department of Immunology, Sungkyunkwan University School of Medicine, Seoul, South Korea

    Tae Jin Kim

  7. Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, Research Institute, National Cancer Center, Gyeonggi, South Korea

    Ho Lee

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Contributions

J.-K.L. and S.Y.K. designed the studies, analyzed the data, and prepared and wrote specific portions of the manuscript. H.-M.N., J.-B.L., J.K., E.-J.P., and K.-M.K. participated in data generation and analysis. T.J.K. provided materials and participated in data generation. H.L. and H.G. designed the studies and wrote part of the manuscript. C.-W.L. designed the studies, supervised the overall project, wrote the manuscript, and performed the final manuscript preparation. All authors provided feedback and agreed on the final manuscript.

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Correspondence to Ho Lee, Heounjeong Go or Chang-Woo Lee.

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Lee, JK., Koo, SY., Nam, HM. et al. Ssu72 is a T-cell receptor-responsive modifier that is indispensable for regulatory T cells. Cell Mol Immunol 18, 1395–1411 (2021). https://doi.org/10.1038/s41423-021-00671-2

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