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T-bet represses TH17 differentiation by preventing Runx1-mediated activation of the gene encoding RORγt

Nature Immunology volume 12, pages 96–104 (2011)Cite this article

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Abstract

Overactive responses by interleukin 17 (IL-17)-producing helper T cells (TH17 cells) are tightly linked to the development of autoimmunity, yet the factors that negatively regulate the differentiation of this lineage remain unknown. Here we report that the transcription factor T-bet suppressed development of the TH17 cell lineage by inhibiting transcription of Rorc (which encodes the transcription factor RORγt). T-bet interacted with the transcription factor Runx1, and this interaction blocked Runx1-mediated transactivation of Rorc. T-bet Tyr304 was required for formation of the T-bet–Runx1 complex, for blockade of Runx1 activity and for inhibition of the TH17 differentiation program. Our data reinforce the idea of master regulators that shape immune responses by simultaneously activating one genetic program while silencing the activity of competing regulators in a common progenitor cell.

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Figure 1: T-bet deficiency promotes IL-17A production in vitro independently of IFN-γ.
Figure 2: T-bet deficiency promotes TH17 responses in the CNS during EAE.
Figure 3: T-bet expression in naive helper T cell precursors and fully differentiated TH17 cells inhibits the TH17 response.
Figure 4: T-bet blocks Runx1-mediated transactivation of the Rorc promoter.
Figure 5: Interaction of T-bet with Runx1.
Figure 6: Runx1 overexpression restores IL-17A production in TH17 cells expressing T-bet.
Figure 7: T-bet Tyr304 is essential for the interaction of T-bet with Runx1 and for inhibition of the TH17 differentiation program.

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Acknowledgements

We thank D. Kozoriz for help in cell sorting; W. Strober (National Institute of Allergy and Infectious Diseases) for retroviral plasmids encoding Runx1 and dominant negative Runx1; S.L. Reiner (University of Pennsylvania) for mice with loxP-flanked Tbx21 alleles; C.B. Wilson (The Bill and Melinda Gates Foundation) for mice with expression of Cre recombinase driven by the Cd4 promoter; and A.-H. Lee, T. Staton-Winslow, M. Greenblatt and M. Wein for critical review of the manuscript. Supported by the US National Institutes of Health (P01 NS038037), the Ragon Institute of MIT, MGH and Harvard (L.H.G.), the National Cancer Research Center (R15-2006-020 to E.S.H.) and the Cancer Research Institute (V.L.).

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Author notes

  1. Xi Chen and Jae-Hyuck Shim: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA

    Vanja Lazarevic, Xi Chen, Jae-Hyuck Shim, Alexandra N Bolm & Laurie H Glimcher

  2. Division of Life and Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, South Korea

    Eun-Sook Hwang & Eunjung Jang

  3. Department of Pediatrics, Seattle Children's Research Institute, Seattle, Washington, USA

    Mohamed Oukka

  4. Center for Neurologic Diseases, Brigham & Women's Hospital, Boston, Massachusetts, USA

    Vijay K Kuchroo

  5. Department of Medicine, Harvard Medical School, and the Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA

    Laurie H Glimcher

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Contributions

V.L. designed and did experiments and prepared the manuscript; X.C. did ChIP assays; J.-H.S. did DNA-precipitation and coimmunoprecipitation assays; E.-S.H. created T-bet mutant retroviral constructs; E.J. did doxycycline transgenic T cell experiments; M.O. generated IL-23R.GFP mice; V.K.K. contributed to discussions and manuscript preparation; A.N.B. provided technical assistance; and L.H.G. supervised the research, designed experiments and participated in preparing the manuscript.

Corresponding authors

Correspondence to Vanja Lazarevic or Laurie H Glimcher.

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Competing interests

L.H.G. is on the Board of Directors and holds equity in Bristol Myers Squibb.

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Lazarevic, V., Chen, X., Shim, JH. et al. T-bet represses TH17 differentiation by preventing Runx1-mediated activation of the gene encoding RORγt. Nat Immunol 12, 96–104 (2011). https://doi.org/10.1038/ni.1969

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