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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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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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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DOI: https://doi.org/10.1038/s41423-021-00671-2
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