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The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation

Abstract

Several subsets of Foxp3+ regulatory T cells (Treg cells) work in concert to maintain immune homeostasis. However, the molecular bases underlying the phenotypic and functional diversity of Treg cells remain obscure. We show that in response to interferon-γ, Foxp3+ Treg cells upregulated the T helper type 1 (TH1)-specifying transcription factor T-bet. T-bet promoted expression of the chemokine receptor CXCR3 on Treg cells, and T-bet+ Treg cells accumulated at sites of TH1 cell–mediated inflammation. Furthermore, T-bet expression was required for the homeostasis and function of Treg cells during type 1 inflammation. Thus, in a subset of CD4+ T cells, the activities of the transcription factors Foxp3 and T-bet are overlaid, which results in Treg cells with unique homeostatic and migratory properties optimized for the suppression of TH1 responses in vivo.

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Figure 1: CXCR3 expression on Treg cells is T-bet dependent.
Figure 2: Treg cells upregulate T-bet in vivo after treatment with anti-CD40.
Figure 3: IFN-γR and STAT1 promote the expression of T-bet and CXCR3 by Treg cells.
Figure 4: Functional characterization of T-bet+ Foxp3+ Treg cells.
Figure 5: Impaired proliferation of T-bet-deficient Treg cells after treatment with anti-CD40.
Figure 6: Impaired homeostasis of T-bet-deficient Treg cells during persistent infection with M. tuberculosis.
Figure 7: T-bet expression in Treg cells is critical for control of TH1 cell–mediated inflammatory responses.

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Acknowledgements

We thank A. Weinmann (University of Washington) for Tbx21−/− mice; A. Rudensky (University of Washington) for Foxp3GFP mice; S. Ziegler (Benaroya Research Institute) for mice with overexpression of thymic stromal lymphopoietin and for Il4−/− and Stat6−/− mice; M. Krishna-Kaja (University of Washington) for splenocytes from Stat1−/− mice; L. Thompson and K. Smigiel for technical assistance; G. Debes, K. Klonowski and J. Hamerman for comments on the manuscript; and M. Warren for administrative assistance. Supported by the US National Institutes of Health (DK072295, AI067750 and AI069889 to D.J.C.), the US Department of Defense (USAMRAA W81XWH-07-0246 to D.J.C.), the Burroughs-Wellcome Fund (K.B.U.) and the Department of Immunology at the University of Washington Medical School (T32-CA009537 to M.A.K.).

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M.A.K., K.B.U. and D.J.C. designed the study, analyzed data and wrote the manuscript, and M.A.K. and D.J.C. did experiments with assistance from N.R.P., J.R.K. and G.T-H.

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Correspondence to Daniel J Campbell.

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Koch, M., Tucker-Heard, G., Perdue, N. et al. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat Immunol 10, 595–602 (2009). https://doi.org/10.1038/ni.1731

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