Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1 (original) (raw)

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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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

Authors

  1. Masahiro Ono
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  2. Hiroko Yaguchi
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  3. Naganari Ohkura
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  4. Issay Kitabayashi
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  5. Yuko Nagamura
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  6. Takashi Nomura
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  7. Yoshiki Miyachi
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  8. Toshihiko Tsukada
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  9. Shimon Sakaguchi
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Correspondence toShimon Sakaguchi.

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Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

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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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Editorial Summary

Immunity tamed

CD25+CD4+ regulatory T cells or 'Tregs' are vital to the immune system, suppressing aberrant or excessive immune responses such as autoimmune disease and allergy. Ono et al. find that Tregs act via the interaction of the transcription factors AML1/Runx1 and Foxp3. This interaction is therefore a potential therapeutic target for controlling immune responses.