Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Shevach, E. M. Regulatory T cells in autoimmmunity. Annu. Rev. Immunol. 18, 423–449 (2000)

    Article  CAS  Google Scholar 

  2. Maloy, K. J. & Powrie, F. Regulatory T cells in the control of immune pathology. Nature Immunol. 2, 816–822 (2001)

    Article  CAS  Google Scholar 

  3. Sakaguchi, S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu. Rev. Immunol. 22, 531–562 (2004)

    Article  CAS  Google Scholar 

  4. Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003)

    Article  ADS  CAS  Google Scholar 

  5. Fontenot, J. D., Gavin, M. A. & Rudensky, A. Y. Foxp3 programs the development and function of CD4+ CD25+ regulatory T cells. Nature Immunol. 4, 330–336 (2003)

    Article  CAS  Google Scholar 

  6. Khattri, R., Cox, T., Yasayko, S. A. & Ramsdell, F. An essential role for Scurfin in CD4+ CD25+ T regulatory cells. Nature Immunol. 4, 337–342 (2003)

    Article  CAS  Google Scholar 

  7. Fontenot, J. D., Rasmussen, J. P., Gavin, M. A. & Rudensky, A. Y. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nature Immunol. 6, 1142–1151 (2005)

    Article  CAS  Google Scholar 

  8. Okuda, T., van Deursen, J., Hiebert, S. W., Grosveld, G. & Downing, J. R. AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell 84, 321–330 (1996)

    Article  CAS  Google Scholar 

  9. Wang, Q. et al. Disruption of the Cbfa2 gene causes necrosis and hemorrhaging in the central nervous system and blocks definitive hematopoiesis. Proc. Natl Acad. Sci. USA 93, 3444–3449 (1996)

    Article  ADS  CAS  Google Scholar 

  10. Taniuchi, I. et al. Differential requirements for Runx proteins in CD4 repression and epigenetic silencing during T lymphocyte development. Cell 111, 621–633 (2002)

    Article  CAS  Google Scholar 

  11. Komine, O. et al. The Runx1 transcription factor inhibits the differentiation of naive CD4+ T cells into the Th2 lineage by repressing GATA3 expression. J. Exp. Med. 198, 51–61 (2003)

    Article  CAS  Google Scholar 

  12. Jain, J., Loh, C. & Rao, A. Transcriptional regulation of the IL-2 gene. Curr. Opin. Immunol. 7, 333–342 (1995)

    Article  CAS  Google Scholar 

  13. Rooney, J. W., Sun, Y. L., Glimcher, L. H. & Hoey, T. Novel NFAT sites that mediate activation of the interleukin-2 promoter in response to T-cell receptor stimulation. Mol. Cell. Biol. 15, 6299–6310 (1995)

    Article  CAS  Google Scholar 

  14. Bruniquel, D. & Schwartz, R. H. Selective, stable demethylation of the interleukin-2 gene enhances transcription by an active process. Nature Immunol. 4, 235–240 (2003)

    Article  CAS  Google Scholar 

  15. Novak, T. J., White, P. M. & Rothenberg, E. V. Regulatory anatomy of the murine interleukin-2 gene. Nucleic Acids Res. 18, 4523–4533 (1990)

    Article  CAS  Google Scholar 

  16. Kitabayashi, I., Yokoyama, A., Shimizu, K. & Ohki, M. Interaction and functional cooperation of the leukemia-associated factors AML1 and p300 in myeloid cell differentiation. EMBO J. 17, 2994–3004 (1998)

    Article  CAS  Google Scholar 

  17. Yagi, H. et al. Crucial role of FOXP3 in the development and function of human CD25+ CD4+ regulatory T cells. Int. Immunol. 16, 1643–1656 (2004)

    Article  CAS  Google Scholar 

  18. Walker, M. R. et al. Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+ CD25- T cells. J. Clin. Invest. 112, 1437–1443 (2003)

    Article  CAS  Google Scholar 

  19. Fontenot, J. D. et al. Regulatory T cell lineage specification by the forkhead transcription factor Foxp3. Immunity 22, 329–341 (2005)

    Article  CAS  Google Scholar 

  20. Ono, M., Shimizu, J., Miyachi, Y. & Sakaguchi, S. Control of autoimmune myocarditis and multiorgan inflammation by glucocorticoid-induced TNF receptor family-related proteinhigh, Foxp3-expressing CD25+ and CD25- regulatory T cells. J. Immunol. 176, 4748–4756 (2006)

    Article  CAS  Google Scholar 

  21. Kanno, Y., Kanno, T., Sakakura, C., Bae, S. C. & Ito, Y. Cytoplasmic sequestration of the polyomavirus enhancer binding protein 2 (PEBP2)/core binding factor α (CBFα) subunit by the leukemia-related PEBP2/CBFβ-SMMHC fusion protein inhibits PEBP2/CBF-mediated transactivation. Mol. Cell. Biol. 18, 4252–4261 (1998)

    Article  CAS  Google Scholar 

  22. Wu, Y. et al. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell 126, 375–387 (2006)

    Article  CAS  Google Scholar 

  23. Thornton, A. M. & Shevach, E. M. CD4+ CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J. Exp. Med. 188, 287–296 (1998)

    Article  CAS  Google Scholar 

  24. Takahashi, T. et al. Immunologic self-tolerance maintained by CD25+ CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state. Int. Immunol. 10, 1969–1980 (1998)

    Article  CAS  Google Scholar 

  25. Brenner, O. et al. Loss of Runx3 function in leukocytes is associated with spontaneously developed colitis and gastric mucosal hyperplasia. Proc. Natl Acad. Sci. USA 101, 16016–16021 (2004)

    Article  ADS  CAS  Google Scholar 

  26. Prokunina, L. et al. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nature Genet. 32, 666–669 (2002)

    Article  CAS  Google Scholar 

  27. Helms, C. et al. A putative RUNX1 binding site variant between SLC9A3R1 and NAT9 is associated with susceptibility to psoriasis. Nature Genet. 35, 349–356 (2003)

    Article  CAS  Google Scholar 

  28. Tokuhiro, S. et al. An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis. Nature Genet. 35, 341–348 (2003)

    Article  CAS  Google Scholar 

Download references

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.

Author information

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
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hiroko Yaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Naganari Ohkura
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Issay Kitabayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yuko Nagamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Takashi Nomura
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yoshiki Miyachi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Toshihiko Tsukada
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shimon Sakaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shimon Sakaguchi.

Ethics declarations

Competing interests

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

Supplementary information

Supplementary Information

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

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature05673

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing
pFad - Phonifier reborn

Pfad - The Proxy pFad of © 2024 Garber Painting. All rights reserved.

Note: This service is not intended for secure transactions such as banking, social media, email, or purchasing. Use at your own risk. We assume no liability whatsoever for broken pages.


Alternative Proxies:

Alternative Proxy

pFad Proxy

pFad v3 Proxy

pFad v4 Proxy