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IRF8: identity-keeper for suppressive Th1-like Treg cells

Cellular & Molecular Immunology volume 15, pages 1080–1081 (2018)Cite this article

Regulatory T (Treg) cells maintain immune homeostasis by inhibiting excessive immune responses. Treg cells control a variety of immune responses, which vary according to the nature of the infection or insult. Treg cells were once thought to be stable; however, many studies now suggest that they have a certain level of flexibility, or plasticity. For example, they deal with various inflammatory conditions by adapting to the environment. Treg cells controlling type I responses express T-bet1 or IRF8,2 whereas those controlling type II responses express IRF4,3 those controlling type III responses express STAT3,4 and those controlling germinal center reactions express Bcl-6.5, 6 In addition, Treg cells residing in visceral adipose tissue express PPAR-γ,7 whereas those residing in skeletal muscle express amphiregulin.8 These tissue-resident Treg cells have specialized roles, including the control of metabolic inflammation and muscle repair.7, 8 This functional plasticity reflects the finding that Treg cells may adjust their phenotype and function in response to the environment in which they reside. Under these conditions, Treg cells coexpress genes that are also expressed by the effector cells they control. Depending on the type of response they control, Treg cells are classified as Th1-like (controlling type I responses), Th2-like (controlling type II responses), or Th17-like (controlling type III responses). Many studies have reported the suppressive and nonsuppressive functions of these plastic Treg cells.

It is unclear whether suppressive Treg cells can convert to nonsuppressive cells. Some studies demonstrate the stable nature of Treg cells, but others reveal their plastic nature. Studies using lineage tracer mice, in which Foxp3 expression is readily monitored using fluorescent proteins, show that Treg cells do not convert to ex-Treg cells (Treg cells that have lost Foxp3 expression) under homeostatic or inflammatory conditions.9, 10 However, other studies using the same technique show that Treg cells can lose both Foxp3 expression and suppressive activity under autoimmune and inflammatory conditions.11, 12

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References

  1. Koch, M. A. et al. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat. Immunol. 10, 595–602 (2009).

    Article  CAS  Google Scholar 

  2. Lee, W., Kim, H. S., Baek, S. Y. & Lee, G. R. Transcription factor IRF8 controls Th1-like regulatory T-cell function. Cell Mol. Immunol. 13, 785–794 (2016).

    Article  CAS  Google Scholar 

  3. Zheng, Y. et al. Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature 458, 351–356 (2009).

    Article  CAS  Google Scholar 

  4. Chaudhry, A. et al. CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science 326, 986–991 (2009).

    Article  CAS  Google Scholar 

  5. Chung, Y. et al. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat. Med 17, 983–988 (2011).

    Article  CAS  Google Scholar 

  6. Linterman, M. A. et al. Foxp3+ follicular regulatory T cells control the germinal center response. Nat. Med 17, 975–982 (2011).

    Article  CAS  Google Scholar 

  7. Cipolletta, D. et al. PPAR-gamma is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature 486, 549–553 (2012).

    Article  CAS  Google Scholar 

  8. Burzyn, D. et al. A special population of regulatory T cells potentiates muscle repair. Cell 155, 1282–1295 (2013).

    Article  CAS  Google Scholar 

  9. Rubtsov, Y. P. et al. Stability of the regulatory T cell lineage in vivo. Science 329, 1667–1671 (2010).

    Article  CAS  Google Scholar 

  10. Levine, A. G. et al. Stability and function of regulatory T cells expressing the transcription factor T-bet. Nature 546, 421–425 (2017).

    Article  CAS  Google Scholar 

  11. Zhou, X. et al. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat. Immunol. 10, 1000–1007 (2009).

    Article  CAS  Google Scholar 

  12. Tsuji, M. et al. Preferential generation of follicular B helper T cells from Foxp3+ T cells in gut Peyer’s patches. Science 323, 1488–1492 (2009).

    Article  CAS  Google Scholar 

  13. Dominguez-Villar, M., Baecher-Allan, C. M. & Hafler, D. A. Identification of T helper type 1-like, Foxp3+ regulatory T cells in human autoimmune disease. Nat. Med 17, 673–675 (2011).

    Article  CAS  Google Scholar 

  14. Kitz, A. & Dominguez-Villar, M. Molecular mechanisms underlying Th1-like Treg generation and function. Cell Mol. Life Sci. 74, 4059–4075 (2017).

    Article  CAS  Google Scholar 

  15. Piconese, S. & Barnaba, V. Stability of regulatory T cells undermined or endorsed by different type-1 cytokines. Adv. Exp. Med Biol. 850, 17–30 (2015).

    Article  CAS  Google Scholar 

  16. Koch, M. A. et al. T-bet(+) Treg cells undergo abortive Th1 cell differentiation due to impaired expression of IL-12 receptor beta2. Immunity 37, 501–510 (2012).

    Article  CAS  Google Scholar 

  17. Lu, L. F. et al. Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell 142, 914–929 (2010).

    Article  CAS  Google Scholar 

  18. Piconese, S. et al. Human OX40 tunes the function of regulatory T cells in tumor and nontumor areas of hepatitis C virus-infected liver tissue. Hepatology 60, 1494–1507 (2014).

    Article  CAS  Google Scholar 

  19. Lin, R. et al. USP4 interacts and positively regulates IRF8 function via K48-linked deubiquitination in regulatory T cells. FEBS Lett. 591, 1677–1686 (2017).

    Article  CAS  Google Scholar 

  20. Carr, T. M., Wheaton, J. D., Houtz, G. M. & Ciofani, M. JunB promotes Th17 cell identity and restrains alternative CD4(+) T-cell programs during inflammation. Nat. Commun. 8, 301 (2017).

    Article  Google Scholar 

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Acknowledgements

This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (NRF-2017R1A2B3008621).

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  1. Department of Life Science, Sogang University, 35 Baekbeom-ro, Mapo-gu, Seoul, 04107, Korea

    Gap Ryol Lee

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Lee, G.R. IRF8: identity-keeper for suppressive Th1-like Treg cells. Cell Mol Immunol 15, 1080–1081 (2018). https://doi.org/10.1038/s41423-018-0044-9

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