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Foxo proteins cooperatively control the differentiation of Foxp3+ regulatory T cells

Nature Immunology volume 11, pages 618–627 (2010)Cite this article

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Abstract

CD4+ regulatory T cells (Treg cells) characterized by expression of the transcription factor Foxp3 have a pivotal role in maintaining immunological tolerance. Here we show that mice with T cell–specific deletion of both the Foxo1 and Foxo3 transcription factors (collectively called 'Foxo proteins' here) developed a fatal multifocal inflammatory disorder due in part to Treg cell defects. Foxo proteins functioned in a Treg cell–intrinsic manner to regulate thymic and transforming growth factor-β (TGF-β)-induced Foxp3 expression, in line with the ability of Foxo proteins to bind to Foxp3 locus and control Foxp3 promoter activity. Transcriptome analyses showed that Foxo proteins regulated the expression of additional Treg cell–associated genes and were essential for inhibiting the acquisition of effector T cell characteristics by Treg cells. Thus, Foxo proteins have crucial roles in specifying the Treg cell lineage.

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Figure 1: The development of a multifocal inflammatory disorder in mice with T cell–specific deletion of Foxo1 and Foxo3.
Figure 2: T cell activation and differentiation in the absence of Foxo1 and Foxo3.
Figure 3: Treg cell development and function in the absence of Foxo1 and Foxo3.
Figure 4: Gene expression and cytokine production in Foxo1−/−Foxo3−/− Treg cells.
Figure 5: Wild-type Treg cells correct the inflammatory disorder of Foxo1−/−Foxo3−/− mice.
Figure 6: Foxo1−/−Foxo3−/− Treg cells do not correct the scurfy-induced immune disorder.
Figure 7: A cell-intrinsic role for Foxo1 and Foxo3 in the control of Foxp3 expression.
Figure 8: Regulation of Foxp3 transcription by Foxo1 and Foxo3.

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Change history

  • 18 May 2010

    In the version of this article initially published online, the final sentence of the “Chromatin immunoprecipitation” paragraph of the Online Methods section was incorrect. The correct sentence is “Primers for analysis of the binding of Foxo1 and Foxo3 to the Foxp3 locus are in Supplementary Table 5.” The error has been corrected for the PDF and HTML versions of this article.

  • 18 May 2010

    In the version of this supplementary file originally posted online, the Supplementary Information file was incorrect. The error has been corrected in this file as of 18 May 2010.

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Acknowledgements

We thank R. Flavell (Yale University) for the Foxp3-RFP mouse strain; S. Ghosh (Columbia University) for luciferase reporter constructs; A. Brunet (Stanford University) for the Foxo3-specific antibody; and A. Rudensky, M. Huse and Y. Zheng for discussions. Supported by the Starr Cancer Consortium (13-A123 to M.O.L.), the National Institute of Arthritis, Musculoskeletal and Skin Diseases (K01 AR053595 to M.O.L.), the Arthritis Foundation (M.O.L.), the Robert A. and Renee E. Belfer Family Foundation (R.A.D.), the Damon-Runyon Cancer Research Foundation (J.-h.P.) and the Rita Allen Foundation (M.O.L.).

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Authors and Affiliations

  1. Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Weiming Ouyang, Omar Beckett, Qian Ma & Ming O Li

  2. Department of Medical Oncology, Department of Medicine and Department of Genetics, Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

    Ji-hye Paik & Ronald A DePinho

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Contributions

W.O. and M.O.L. designed the research and analyzed the data; W.O., O.B. and Q.M. did experiments; R.A.D. and J.-h.P. provided the mouse strain with floxed Foxo3 and feedback on the manuscript; and W.O. and M.O.L. wrote the manuscript.

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Correspondence to Ming O Li.

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Ouyang, W., Beckett, O., Ma, Q. et al. Foxo proteins cooperatively control the differentiation of Foxp3+ regulatory T cells. Nat Immunol 11, 618–627 (2010). https://doi.org/10.1038/ni.1884

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