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Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1

Nature volume 446, pages 685–689 (2007)Cite this article

Abstract

Naturally arising CD25+CD4+ regulatory T cells (TR cells) are engaged in the maintenance of immunological self-tolerance and immune homeostasis by suppressing aberrant or excessive immune responses, such as autoimmune disease and allergy1,2,3. TR cells specifically express the transcription factor Foxp3, a key regulator of TR-cell development and function. Ectopic expression of Foxp3 in conventional T cells is indeed sufficient to confer suppressive activity, repress the production of cytokines such as interleukin-2 (IL-2) and interferon-gamma (IFN-γ), and upregulate TR-cell-associated molecules such as CD25, cytotoxic T-lymphocyte-associated antigen-4, and glucocorticoid-induced TNF-receptor-family-related protein4,5,6,7. However, the method by which Foxp3 controls these molecular events has yet to be explained. Here we show that the transcription factor AML1 (acute myeloid leukaemia 1)/Runx1 (Runt-related transcription factor 1), which is crucially required for normal haematopoiesis including thymic T-cell development8,9,10,11, activates IL-2 and IFN-γ gene expression in conventional CD4+ T cells through binding to their respective promoters. In natural TR cells, Foxp3 interacts physically with AML1. Several lines of evidence support a model in which the interaction suppresses IL-2 and IFN-γ production, upregulates TR-cell-associated molecules, and exerts suppressive activity. This transcriptional control of TR-cell function by an interaction between Foxp3 and AML1 can be exploited to control physiological and pathological T-cell-mediated immune responses.

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Figure 1: AML1/Runx1 enhances IL-2 expression through binding to the IL-2 promoter in activated T cells.
Figure 2: Foxp3 interacts physically with AML1.
Figure 3: Foxp3 represses AML1-induced IL-2 expression by interacting with AML1.
Figure 4: Foxp3 requires interaction with AML1 to confer T R -cell phenotype and function on conventional T cells.

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Acknowledgements

We thank M. Kakino, R. Ishii and M. Yoshida for technical assistance; F. Rawle for valuable comments on the manuscript; T. Kitamura for the pMCsIg retroviral vector; M. Onodera for the pGCSamIN retroviral vector; and F. Macian for the NFAT-CA construct.

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Author notes

  1. Masahiro Ono, Hiroko Yaguchi and Naganari Ohkura: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Experimental Pathology, Institute for Frontier Medical Sciences, and,

    Masahiro Ono, Takashi Nomura & Shimon Sakaguchi

  2. Department of Dermatology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan,

    Masahiro Ono & Yoshiki Miyachi

  3. Tumor Endocrinology Project, and,,

    Hiroko Yaguchi, Naganari Ohkura, Yuko Nagamura & Toshihiko Tsukada

  4. Molecular Oncology Division, National Cancer Center Research Institute, Chuo-ku, Tokyo, 104-0045, Japan,

    Issay Kitabayashi

  5. Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Kawaguchi 332-0012, Japan,

    Shimon Sakaguchi

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Correspondence to Shimon Sakaguchi.

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This file contains Supplementary Figures S1-S12, Supplementary Discussion, Supplementary Methods and additional references. (PDF 11257 kb)

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Ono, M., Yaguchi, H., Ohkura, N. et al. Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1. Nature 446, 685–689 (2007). https://doi.org/10.1038/nature05673

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