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Runx-CBFβ complexes control expression of the transcription factor Foxp3 in regulatory T cells

Nature Immunology volume 10, pages 1170–1177 (2009)Cite this article

Abstract

The transcription factor Foxp3 has an indispensable role in establishing stable transcriptional and functional programs of regulatory T cells (Treg cells). Loss of Foxp3 expression in mature Treg cells results in a failure of suppressor function, yet the molecular mechanisms that ensure steady, heritable Foxp3 expression in the Treg cell lineage remain unknown. Using Treg cell–specific gene targeting, we found that complexes of the transcription factors Runx and CBFβ were required for maintenance of Foxp3 mRNA and protein expression in Treg cells. Consequently, mice lacking CBFβb exclusively in the Treg cell lineage had a moderate lymphoproliferative syndrome. Thus, Runx-CBFβ complexes maintain stable high expression of Foxp3 and serve as an essential determinant of Treg cell lineage stability.

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Figure 1: Characterization of Cbfbfl/wtFoxp3YFP-Cre mice.
Figure 2: Histopathology of Cbfbfl/flFoxp3YFP-Cre mice.
Figure 3: Characterization of Treg cells from Cbfbfl/flFoxp3YFP-Cre mice.
Figure 4: CBFβ is required for the maintenance of Foxp3 expression in Treg cells.
Figure 5: Runx-CBFβ complexes occupy the Foxp3 promoter and a conserved noncoding sequence element in the Foxp3 locus.
Figure 6: CBFβ ablation in Treg cells results in less permissive H3-K4me3 and concomitantly more nonpermissive H3-K9me3 chromatin modifications at the Foxp3 locus.
Figure 7: Ectopic expression of Foxp3 in peripheral CBFβ-deficient T cells induces a characteristic Treg cell phenotype.

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Acknowledgements

We thank M. Tone (University of Pennsylvania) for the reporter construct containing the Foxp3 promoter; K. Forbush, T. Chu and L. Karpik for managing the mouse colony; and I. Taniuchi, Y. Tone and M. Tone for advice. Supported by the National Institutes of Health (A.Y.R.), the Arthritis Foundation (D.R.), the Leukemia and Lymphoma Society (T.E.), the Helen and Martin Kimmel Center for Stem Cell Biology (M.M.W.C.) and the Howard Hughes Medical Institute (A.Y.R. and D.R.L).

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  1. Dipayan Rudra & Alexander Y Rudensky

    Present address: Present address: Howard Hughes Medical Institute and Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, USA.,

Authors and Affiliations

  1. Howard Hughes Medical Institute, University of Washington, Seattle, Washington, USA

    Dipayan Rudra, Mark M W Chong, Dan R Littman & Alexander Y Rudensky

  2. Department of Immunology, University of Washington, Seattle, Washington, USA

    Dipayan Rudra & Alexander Y Rudensky

  3. New York University School of Medicine, New York, New York, USA

    Takeshi Egawa, Mark M W Chong & Dan R Littman

  4. Department of Comparative Medicine, University of Washington, Seattle, Washington, USA

    Piper Treuting

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  1. Dipayan Rudra
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  2. Takeshi Egawa
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Contributions

D.R. designed and did experiments, analyzed the data and cowrote the manuscript with A.Y.R.; T.E., M.M.W.C. and D.R.L. generated and analyzed Runx1fl/flFoxp3YFP-Cre mice and Cbfbfl/flCD4-Cre+ mice; P.T. did histopathology analysis; and A.Y.R. designed experiments with D.R., analyzed the data and cowrote the manuscript with D.R.

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Correspondence to Alexander Y Rudensky.

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Rudra, D., Egawa, T., Chong, M. et al. Runx-CBFβ complexes control expression of the transcription factor Foxp3 in regulatory T cells. Nat Immunol 10, 1170–1177 (2009). https://doi.org/10.1038/ni.1795

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