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For antigen-specific effector or Foxp3+ regulatory T cell fate, cyclin-dependent kinases hold the trump card

Cellular & Molecular Immunology volume 17, pages 310–312 (2020)Cite this article

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Forkhead box p3+ (Foxp3+) regulatory T cells (Tregs) are indispensable for immune homeostasis and for maintaining immune tolerance. Several studies have confirmed that injection of a T cell population depleted of Tregs causes autoimmunity, rejection of grafts and inflammatory disorders, whereas reconstitution with Tregs inhibits these pathogenic processes. Over the last two decades, intense efforts have been made to identify Treg subsets, Treg differentiation processes, and the molecular signatures and regulators that determine Treg lineage specificity and stability.1,2,3,4,5,6

Several lines of evidence clearly demonstrate that Foxp3+ Tregs do not constitute a homogeneous population, and various subsets of Tregs, such as thymic Tregs (tTregs), in vitro-generated Tregs (iTregs), and peripherally induced Tregs (pTregs), have been identified.5 In addition to Foxp3, epigenetic factors and metabolic processes play key roles in maintaining Treg identity and function, and mediate the switch between effector T cells and Tregs.6,7,8 In fact, Tregs require phosphatase and tensin homolog (PTEN) for stability and for maintaining the metabolic balance between glycolysis and mitochondrial functions.9 A recent report argues that mitochondrial complex III is indispensable for the suppressive function of Tregs, citing loss of complex III in Tregs triggering enhanced levels of metabolites 2-hydroxyglutarate (2-HG) and succinate, thereby blocking the ten-eleven translocation (TET) family of DNA demethylases and resulting in DNA hypermethylation and the repression of several transcripts required for Treg function.10,11

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Fig. 1: Cyclin-dependent kinases mitigate the conversion of antigen-specific effector T cells into Foxp3+ regulatory T cells.

References

  1. Knochelmann, H. M. et al. When worlds collide: Th17 and Treg cells in cancer and autoimmunity. Cell. Mol. Immunol. 15, 458–469 (2018).

    Article  CAS  PubMed Central  Google Scholar 

  2. Sakaguchi, S., Miyara, M., Costantino, C. M. & Hafler, D. A. FOXP3+ regulatory T cells in the human immune system. Nat. Rev. Immunol. 10, 490–500 (2010).

    Article  CAS  Google Scholar 

  3. Lu, L., Barbi, J. & Pan, F. The regulation of immune tolerance by FOXP3. Nat. Rev. Immunol. 17, 703–717 (2017).

    Article  CAS  PubMed Central  Google Scholar 

  4. Ferreira, L. M. R., Muller, Y. D., Bluestone, J. A. & Tang, Q. Next-generation regulatory T cell therapy. Nat. Rev. Drug Discov. 18, 749–769 (2019).

    Article  CAS  Google Scholar 

  5. Wing, J. B., Tanaka, A. & Sakaguchi, S. Human FOXP3+ regulatory T cell heterogeneity and function in autoimmunity and cancer. Immunity 50, 302–316 (2019).

    Article  CAS  Google Scholar 

  6. Ohkura, N., Kitagawa, Y. & Sakaguchi, S. Development and maintenance of regulatory T cells. Immunity 38, 414–423 (2013).

    Article  CAS  Google Scholar 

  7. Zhang, X., Liu, J. & Cao, X. Metabolic control of T-cell immunity via epigenetic mechanisms. Cell. Mol. Immunol. 15, 203–205 (2018).

    Article  Google Scholar 

  8. Wei, G. et al. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 30, 155–167 (2009).

    Article  PubMed Central  Google Scholar 

  9. Shrestha, S. et al. Treg cells require the phosphatase PTEN to restrain TH1 and TFH cell responses. Nat. Immunol. 16, 178–187 (2015).

    Article  CAS  PubMed Central  Google Scholar 

  10. Weinberg, S. E. et al. Mitochondrial complex III is essential for suppressive function of regulatory T cells. Nature 565, 495–499 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  11. Das, M., Alzaid, F. & Bayry, J. Regulatory T cells under the mercy of mitochondria. Cell Metab. 29, 243–245 (2019).

    Article  CAS  Google Scholar 

  12. Strainic, M. G., Shevach, E. M., An, F., Lin, F. & Medof, M. E. Absence of signaling into CD4+ cells via C3aR and C5aR enables autoinductive TGF-β1 signaling and induction of Foxp3+ regulatory T cells. Nat. Immunol. 14, 162–171 (2013).

    Article  CAS  Google Scholar 

  13. Xu, T. et al. Metabolic control of TH17 and induced Treg cell balance by an epigenetic mechanism. Nature 548, 228–233 (2017).

    Article  CAS  PubMed Central  Google Scholar 

  14. Akamatsu, M. et al. Conversion of antigen-specific effector/memory T cells into Foxp3-expressing Treg cells by inhibition of CDK8/19. Sci. Immunol. 4, eaaw2707 (2019).

    Article  CAS  Google Scholar 

  15. Dannappel, M. V., Sooraj, D., Loh, J. J. & Firestein, R. Molecular and in vivo functions of the CDK8 and CDK19 kinase modules. Front. Cell Dev. Biol. 6, 171 (2018).

    Article  Google Scholar 

  16. Whittaker, S. R., Mallinger, A., Workman, P. & Clarke, P. A. Inhibitors of cyclin-dependent kinases as cancer therapeutics. Pharmacol. Ther. 173, 83–105 (2017).

    Article  CAS  PubMed Central  Google Scholar 

  17. Chen, M. et al. CDK8/19 Mediator kinases potentiate induction of transcription by NFκB. Proc. Natl Acad. Sci. USA 114, 10208–10213 (2017).

    Article  CAS  Google Scholar 

  18. Sharabi, A. et al. Regulatory T cells in the treatment of disease. Nat. Rev. Drug Discov. 17, 823–844 (2018).

    Article  CAS  Google Scholar 

  19. Romano, M., Fanelli, G., Albany, C. J., Giganti, G. & Lombardi, G. Past, present, and future of regulatory T cell therapy in transplantation and autoimmunity. Front. Immunol. 10, 43 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  20. Abbas, A. K., Trotta, E., Simeonov, R., Marson, D. & Bluestone, A. J.A. Revisiting IL-2: biology and therapeutic prospects. Sci. Immunol. 3, eaat1482 (2018).

    Article  PubMed Central  Google Scholar 

  21. Clarke, P. A. et al. Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases. elife 5, e20722 (2016).

    Article  PubMed Central  Google Scholar 

  22. Zhao, H., Liao, X. & Kang, Y. Tregs: where we are and what comes next? Front. Immunol. 8, 1578 (2017).

    Article  PubMed Central  Google Scholar 

  23. Sharma, M. et al. Regulatory T cells induce activation rather than suppression of human basophils. Sci. Immunol. 3, eaan0829 (2018).

    Article  Google Scholar 

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Acknowledgements

The work was supported by ANR-19-CE17-0021 (BASIN), Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, and Université Paris Descartes, Paris, France.

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Authors and Affiliations

  1. Neuroimmunology & peptide therapy, Biotechnology and cell signaling, CNRS-University of Strasbourg, Illkirch, 67412, Strasbourg, France

    Srinivasa Reddy Bonam

  2. Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, Equipe-Immunopathologie et Immunointervention Thérapeutique, Sorbonne Université, Université Paris Descartes, Sorbonne Paris Cité, Paris, F-75006, France

    Jagadeesh Bayry

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S.R.B. and J.B. performed the literature search and analyses and drafted the manuscript.

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Correspondence to Jagadeesh Bayry.

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Bonam, S.R., Bayry, J. For antigen-specific effector or Foxp3+ regulatory T cell fate, cyclin-dependent kinases hold the trump card. Cell Mol Immunol 17, 310–312 (2020). https://doi.org/10.1038/s41423-019-0349-3

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