Abstract
The transcription factor Foxp3 is involved in the differentiation, function and survival of CD4+CD25+ regulatory T (Treg) cells. Details of the mechanism underlying the induction of Foxp3 expression remain unknown, because studies of the transcriptional regulation of the Foxp3 gene are limited by the small number of Treg cells in mononuclear cell populations. Here we have generated a model system for analyzing Foxp3 induction and, by using this system with primary T cells, we have identified an enhancer element in this gene. The transcription factors Smad3 and NFAT are required for activity of this Foxp3 enhancer, and both factors are essential for histone acetylation in the enhancer region and induction of Foxp3. These biochemical properties that define Foxp3 expression explain many of the effects of transforming growth factor-β on the function of Foxp3+ Treg cells.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Shevach, E.M. Regulatory T cells in autoimmmunity. Annu. Rev. Immunol. 18, 423–449 (2000).
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).
Fontenot, J.D., Gavin, M.A. & Rudensky, A.Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4, 330–336 (2003).
Brunkow, M.E. et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat. Genet. 27, 68–73 (2001).
Bennett, C.L. et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet. 27, 20–21 (2001).
Gavin, M.A. et al. Foxp3-dependent programme of regulatory T-cell differentiation. Nature 445, 771–775 (2007).
Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).
Khattri, R., Cox, T., Yasayko, S.A. & Ramsdell, F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat. Immunol. 4, 337–342 (2003).
Wan, Y.Y. & Flavell, R.A. Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression. Nature 445, 766–770 (2007).
Wu, Y. et al. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell 126, 375–387 (2006).
Bettelli, E., Dastrange, M. & Oukka, M. Foxp3 interacts with nuclear factor of activated T cells and NF-κB to repress cytokine gene expression and effector functions of T helper cells. Proc. Natl. Acad. Sci. USA 102, 5138–5143 (2005).
Ono, M. et al. Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1. Nature 446, 685–689 (2007).
Li, B. et al. FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression. Proc. Natl. Acad. Sci. USA 104, 4571–4576 (2007).
Mantel, P.Y. et al. Molecular mechanisms underlying FOXP3 induction in human T cells. J. Immunol. 176, 3593–3602 (2006).
Kim, H.P. & Leonard, W.J. CREB/ATF-dependent T cell receptor–induced FoxP3 gene expression: a role for DNA methylation. J. Exp. Med. 204, 1543–1551 (2007).
Chen, W. et al. Conversion of peripheral CD4+CD25− naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J. Exp. Med. 198, 1875–1886 (2003).
Fantini, M.C. et al. Cutting edge: TGF-β induces a regulatory phenotype in CD4+CD25− T cells through Foxp3 induction and down-regulation of Smad7. J. Immunol. 172, 5149–5153 (2004).
Tone, Y. et al. OX40 gene expression is upregulated by chromatin remodeling in its promoter region containing Sp1/Sp3, YY1 and NF-κB binding sites. J. Immunol. 179, 1760–1767 (2007).
Tone, M., Powell, M.J., Tone, Y., Thompson, S.A. & Waldmann, H. IL-10 gene expression is controlled by the transcription factors Sp1 and Sp3. J. Immunol. 165, 286–291 (2000).
Jain, J., McCaffrey, P.G., Valge-Archer, V.E. & Rao, A. Nuclear factor of activated T cells contains Fos and Jun. Nature 356, 801–804 (1992).
Li, M.O., Sanjabi, S. & Flavell, R.A. Transforming growth factor-β controls development, homeostasis, and tolerance of T cells by regulatory T cell–dependent and –independent mechanisms. Immunity 25, 455–471 (2006).
Massague, J., Seoane, J. & Wotton, D. Smad transcription factors. Genes Dev. 19, 2783–2810 (2005).
Zhu, Y., Richardson, J.A., Parada, L.F. & Graff, J.M. Smad3 mutant mice develop metastatic colorectal cancer. Cell 94, 703–714 (1998).
Jinnin, M., Ihn, H. & Tamaki, K. Characterization of SIS3, a novel specific inhibitor of Smad3, and its effect on transforming growth factor-β1–induced extracellular matrix expression. Mol. Pharmacol. 69, 597–607 (2006).
Licona-Limon, P. & Soldevila, G. The role of TGF-β superfamily during T cell development: new insights. Immunol. Lett. 109, 1–12 (2007).
Zou, W. Regulatory T cells, tumour immunity and immunotherapy. Nat. Rev. Immunol. 6, 295–307 (2006).
Peters, N. & Sacks, D. Immune privilege in sites of chronic infection: Leishmania and regulatory T cells. Immunol. Rev. 213, 159–179 (2006).
Cobbold, S.P. et al. Induction of FoxP3+ regulatory T cells in the periphery of T cell receptor transgenic mice tolerized to transplants. J. Immunol. 172, 6003–6010 (2004).
Burchill, M.A., Yang, J., Vogtenhuber, C., Blazar, B.R. & Farrar, M.A. IL-2 receptor β-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells. J. Immunol. 178, 280–290 (2007).
Davidson, T.S., Dipaolo, R.J., Andersson, J. & Shevach, E.M. Cutting edge: IL-2 is essential for TGF-β–mediated induction of Foxp3+ T regulatory cells. J. Immunol. 178, 4022–4026 (2007).
Frohman, M.A., Dush, M.K. & Martin, G.R. Rapid production of full-length cDNAs from rare transcripts: amplification using a single gene-specific oligonucleotide primer. Proc. Natl. Acad. Sci. USA 85, 8998–9002 (1988).
Acknowledgements
This work was supported in part by the US National Institutes of Health (M.L.T. and M.I.G.).
Author information
Authors and Affiliations
Contributions
Y.T., K.F. and M.T. designed and carried out most of the experiments; Y.K. provided primary T cells; M.L.T. and M.I.G. provided intellectual guidance on the study design; and M.I.G. and M.T. wrote the manuscript.
Corresponding author
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–8 (PDF 305 kb)
Rights and permissions
About this article
Cite this article
Tone, Y., Furuuchi, K., Kojima, Y. et al. Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer. Nat Immunol 9, 194–202 (2008). https://doi.org/10.1038/ni1549
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ni1549
This article is cited by
-
A lncRNA Dleu2-encoded peptide relieves autoimmunity by facilitating Smad3-mediated Treg induction
EMBO Reports (2024)
-
The regulation and differentiation of regulatory T cells and their dysfunction in autoimmune diseases
Nature Reviews Immunology (2024)
-
Epigenetic reprogramming of T cells: unlocking new avenues for cancer immunotherapy
Cancer and Metastasis Reviews (2024)
-
Tumor-derived exosomes induce initial activation by exosomal CD19 antigen but impair the function of CD19-specific CAR T-cells via TGF-β signaling
Frontiers of Medicine (2023)
-
Association study between polymorphisms in MIA3, SELE, SMAD3 and CETP genes and coronary artery disease in an Iranian population
BMC Cardiovascular Disorders (2022)