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Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer

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.

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Figure 1: Foxp3 expression in EL4 and CD4+ T cells.
Figure 2: Activity and histone acetylation in the Foxp3 promoter.
Figure 3: Identification and characterization of the Foxp3 enhancer.
Figure 4: Nucleotide sequence of the Foxp3 enhancer and binding of NFAT to the enhancer.
Figure 5: Requirement for TGF-β–Smad3 signaling in histone acetylation and activity of the Foxp3 enhancer.
Figure 6: Maintenance of Foxp3 expression.
Figure 7: Smad3 and NFAT are required for induction of Foxp3 expression.
Figure 8: The Foxp3 enhancer core sequence is highly conserved and histone H4 molecules in this region are highly acetylated.

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Acknowledgements

This work was supported in part by the US National Institutes of Health (M.L.T. and M.I.G.).

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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.

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Correspondence to Masahide Tone.

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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

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