The DOI matches its Crossref record; 31 of the 31 references it cites were found in a registry or an index.
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 cells60.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [60]
In the citing paper
“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]
Citations
Cites
Control of Regulatory T Cell Development by the Transcription Factor Foxp3
Hori, S., Nomura, T., & Sakaguchi, S. (2003) · Science · doi:10.1126/science.1079490 · Cited by 8,187
Foxp3 programs the development and function of CD4+CD25+ regulatory T cells
Fontenot, J. D., Gavin, M. A., & Rudensky, A. Y. (2003) · Nature Immunology · doi:10.1038/ni904 · Cited by 7,745
Chen, W., Jin, W., Hardegen, N. J., Lei, K.-J., Li, L., Marinos, N. J., McGrady, G., & Wahl, S. M. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20030152 · Cited by 4,678
Frohman, M. A., Dush, M. K., & Martin, G. R. (1988) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.85.23.8998 · Cited by 4,554
Bennett, C. L., Christie, J., Ramsdell, F., Brunkow, M., Ferguson, P., Whitesell, L., Kelly, T., Saulsbury, F., Chance, P., & Ochs, H. (2001) · Nature Genetics · doi:10.1038/83713 · Cited by 3,576
Sakaguchi, S. (2003) · Annual Review of Immunology · doi:10.1146/annurev.immunol.21.120601.141122 · Cited by 3,315
An essential role for Scurfin in CD4+CD25+ T regulatory cells
Khattri, R., Cox, T., Yasayko, S.-A., & Ramsdell, F. (2003) · Nature Immunology · doi:10.1038/ni909 · Cited by 2,860
Brunkow, M. E., Jeffery, E. W., Hjerrild, K. A., Paeper, B. W., Clark, L. B., Yasayko, S.-A., Wilkinson, J. E., Galas, D. J., Ziegler, S. F., & Ramsdell, F. (2001) · Nature Genetics · doi:10.1038/83784 · Cited by 2,628
Smad transcription factorsPreprint
Massagué, J., Seoane, J., & Wotton, D. (2005) · Genes & Development · doi:10.1101/gad.1350705 · Cited by 2,519
Regulatory T cells, tumour immunity and immunotherapy
Zou, W. (2006) · Nature reviews. Immunology · doi:10.1038/nri1806 · Cited by 2,135
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Sorted by citations
Differentiation of Effector CD4 T Cell Populations
Zhu, J., Yamane, H., & Paul, W. E. (2010) · Annual Review of Immunology · doi:10.1146/annurev-immunol-030409-101212 · Cited by 3,452
Regulatory T cells: mechanisms of differentiation and function
Josefowicz, S. Z., Lu, L.-F., & Rudensky, A. Y. (2012) · Annual Review of Immunology · doi:10.1146/annurev.immunol.25.022106.141623 · Cited by 2,866
Transforming Growth Factor-β Signaling in Immunity and Cancer
Batlle, E., & Massagué, J. (2019) · Immunity · doi:10.1016/j.immuni.2019.03.024 · Cited by 2,366
CD4 T cells: fates, functions, and faults
Zhu, J., & Paul, W. E. (2008) · Blood · doi:10.1182/blood-2008-05-078154 · Cited by 1,915
CD4 + T Cells: Differentiation and Functions
Luckheeram, R. V., Zhou, R., Verma, A. D., & Xia, B. (2012) · Clinical and Developmental Immunology · doi:10.1155/2012/925135 · Cited by 1,381
Metadata
- 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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