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 (T(reg)) 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 T(reg) 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-beta on the function of Foxp3+ T(reg) cells.
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In naïve CD4+ T cells, TGF-β/Smad3 signaling activates Foxp3, which encodes a master transcription factor that directs differentiation into activated CD4+Foxp3+CD25+ Treg cells.
“In naïve CD4+ T cells, TGF-β/Smad3 signaling activates Foxp3, which encodes a master transcription factor that directs differentiation into activated CD4+Foxp3+CD25+ Treg cells60.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [60]
TGF-β in the presence of IL-2 promotes functional differentiation and survival of CD4+ Treg cells.
“Importantly, TGF-β in the presence of IL-2 promotes functional differentiation and survival of CD4+ Treg cells.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [60]
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- Authors
- Tone, Y., Furuuchi, K., Kojima, Y., Tykocinski, M. L., Greene, M. I., & Tone, M.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Tone, Masahide
- Venue
- Nature Immunology
- Published
- 2007-12-23
- Volume
- 9
- Issue
- 2
- Pages
- 194-202
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- OpenAlex
- W2019077533
- Cited by
- 807
- References
- 31
- Citations by year
- 2026: 16 · 2025: 17 · 2024: 32 · 2023: 34 · 2022: 35 · 2021: 41 · 2020: 45 · 2019: 49 · 2018: 44 · 2017: 45 · 2016: 47 · 2015: 54 · 2014: 45 · 2013: 64 · 2012: 37
- FWCI
- 17.12
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- Foxp3, regulatory T cells, Smad3, NFAT, transcriptional regulation, histone acetylation, TGF-beta, CD4+CD25+ T cells, transcription factor cooperation
- MeSH terms
- Animals, Base Sequence, Enhancer Elements, Genetic, Gene Expression Regulation, Molecular Sequence Data, Cell Line, Tumor, T-Lymphocytes, Regulatory, NFATC Transcription Factors, Mice, Forkhead Transcription Factors, Smad3 Protein
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