Foxp3 occupancy and regulation of key target genes during T-cell stimulation
Open accessAbstract
Foxp3+CD4+CD25+ regulatory T (T(reg)) cells are essential for the prevention of autoimmunity. T(reg) cells have an attenuated cytokine response to T-cell receptor stimulation, and can suppress the proliferation and effector function of neighbouring T cells. The forkhead transcription factor Foxp3 (forkhead box P3) is selectively expressed in T(reg) cells, is required for T(reg) development and function, and is sufficient to induce a T(reg) phenotype in conventional CD4+CD25- T cells. Mutations in Foxp3 cause severe, multi-organ autoimmunity in both human and mouse. FOXP3 can cooperate in a DNA-binding complex with NFAT (nuclear factor of activated T cells) to regulate the transcription of several known target genes. However, the global set of genes regulated directly by Foxp3 is not known and consequently, how this transcription factor controls the gene expression programme for T(reg) function is not understood. Here we identify Foxp3 target genes and report that many of these are key modulators of T-cell activation and function. Remarkably, the predominant, although not exclusive, effect of Foxp3 occupancy is to suppress the activation of target genes on T-cell stimulation. Foxp3 suppression of its targets appears to be crucial for the normal function of T(reg) cells, because overactive variants of some target genes are known to be associated with autoimmune disease.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Genes affected by positive or negative regulators significantly overlap with genes bound by key CD4+ transcription factors Foxp3, Batf, Irf4, and ROR-γt.
“The genes affected by either positive or negative regulators also significantly overlap with those bound by key CD4+ transcription factors (e.g., Foxp326,27, Batf, Irf4, and ROR-γt28,29, Xiao et al., unpublished data).”
From Dynamic regulatory network controlling TH17 cell differentiation (2013) · cites this paper as [26]
Cites
KEGG: Kyoto Encyclopedia of Genes and Genomes
Kanehisa, M. (2000) · Nucleic Acids Research · doi:10.1093/nar/28.1.27 · Cited by 37,077 · see citing works
KEGG: Kyoto Encyclopedia of Genes and Genomes
Ogata, H., Goto, S., Sato, K., Fujibuchi, W., Bono, H., & Kanehisa, M. (1999) · Nucleic Acids Research · doi:10.1093/nar/27.1.29 · Cited by 31,232 · see citing works
Control of Regulatory T Cell Development by the Transcription Factor <i>Foxp3</i>
Hori, S., Nomura, T., & Sakaguchi, S. (2003) · Science · doi:10.1126/science.1079490 · Cited by 8,187 · see citing works
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 · see citing works
Park, J., Adoro, S., Guinter, T. I., Erman, B., Alag, A., Catálfamo, M., Kimura, M. Y., Cui, Y., Lucas, P. J., Gress, R. E., et al. (2010) · Nature Immunology · doi:10.1038/ni.1840 · Cited by 5,835 · see citing works
Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M., & Toda, M. (1995) · The Journal of Immunology · doi:10.4049/jimmunol.155.3.1151 · Cited by 5,608 · see citing works
The Role of Tumoral FOXP3 on Cell Proliferation, Migration, and Invasion in Gastric Cancer
Zhang, L., Xu, J., Zhang, X., Zhang, Y., Wang, L., Huang, X., & Xu, Z. (2017) · Cellular Physiology and Biochemistry · doi:10.1159/000479442 · Cited by 4,090 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Polycomb complexes repress developmental regulators in murine embryonic stem cells
Boyer, L. A., Plath, K., Zeitlinger, J., Brambrink, T., Medeiros, L. A., Lee, T. I., Levine, S. S., Wernig, M., Tajonar, A., Ray, M. K., et al. (2006) · Nature · doi:10.1038/nature04733 · Cited by 2,518 · see citing works
Self-citationRegulatory T Cell Lineage Specification by the Forkhead Transcription Factor Foxp3
Fontenot, J. D., Rasmussen, J. P., Williams, L. M., Dooley, J., Farr, A. G., & Rudensky, A. Y. (2005) · Immunity · doi:10.1016/j.immuni.2005.01.016 · Cited by 2,254 · see citing works
Transcriptional regulatory code of a eukaryotic genome
Harbison, C. T., Gordon, D. B., Lee, T. I., Rinaldi, N. J., MacIsaac, K. D., Danford, T., Hannett, N. M., Tagne, J., Reynolds, D. B., Yoo, J. Y., et al. (2004) · Nature · doi:10.1038/nature02800 · Cited by 2,116 · see citing works
Self-citationCD4+CD25+ suppressor T cells: more questions than answers
Shevach, E. M. (2002) · Nature reviews. Immunology · doi:10.1038/nri821 · Cited by 2,097 · see citing works
Wildin, R. S., Ramsdell, F., Peake, J., Faravelli, F., Casanova, J., Buist, N. R. M., Levy‐Lahad, E., Mazzella, M., Goulet, O., Perroni, L., et al. (2001) · Nature Genetics · doi:10.1038/83707 · Cited by 1,916 · see citing works
Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide
Jordan, M. S., Boesteanu, A. C., Reed, A. J., Petrone, A. L., Holenbeck, A. E., Lerman, M. A., Naji, A., & Caton, A. J. (2001) · Nature Immunology · doi:10.1038/86302 · Cited by 1,661 · see citing works
A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes
Bottini, N., Musumeci, L., Alonso, A., Rahmouni, S., Nika, K., Rostamkhani, M., MacMurray, J. P., Meloni, T., Lucarelli, P., Pellecchia, M., et al. (2004) · Nature Genetics · doi:10.1038/ng1323 · Cited by 1,419 · see citing works
CD4+CD25+ Immunoregulatory T Cells
McHugh, R. S., Whitters, M. J., Piccirillo, C. A., Young, D. A., Shevach, E. M., Collins, M., & Byrne, M. C. (2002) · Immunity · doi:10.1016/s1074-7613(02)00280-7 · Cited by 1,395 · see citing works
Inducing and expanding regulatory T cell populations by foreign antigen
Kretschmer, K., Apostolou, I., Hawiger, D., Khazaie, K., Nussenzweig, M. C., & von Boehmer, H. (2005) · Nature Immunology · doi:10.1038/ni1265 · Cited by 1,240 · see citing works
Self-citationFOXP3 Controls Regulatory T Cell Function through Cooperation with NFAT
Wu, Y., Borde, M., Heissmeyer, V., Feuerer, M., Lapan, A. D., Stroud, J. C., Bates, D. L., Guo, L., Han, A., Ziegler, S. F., et al. (2006) · Cell · doi:10.1016/j.cell.2006.05.042 · Cited by 1,188 · see citing works
Mechanisms of suppression by suppressor T cells
von Boehmer, H. (2005) · Nature Immunology · doi:10.1038/ni1180 · Cited by 1,005 · see citing works
Iellem, A., Mariani, M., Lang, R., Recalde, H. R., Panina‐Bordignon, P., Sinigaglia, F., & D’Ambrosio, D. (2001) · The Journal of Experimental Medicine · doi:10.1084/jem.194.6.847 · Cited by 915 · see citing works
Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant
Vang, T., Congia, M., Macis, M. D., Musumeci, L., Orrù, V., Zavattari, P., Nika, K., Tautz, L., Taskén, K., Cucca, F., et al. (2005) · Nature Genetics · doi:10.1038/ng1673 · Cited by 724 · see citing works
Scurfin (FOXP3) Acts as a Repressor of Transcription and Regulates T Cell Activation
Schubert, L. A., Jeffery, E. W., Zhang, Y., Ramsdell, F., & Ziegler, S. F. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m104521200 · Cited by 547 · see citing works
A role for Dicer in immune regulation
Cobb, B. S., Hertweck, A., Smith, J. C., O’Connor, E., Graf, D., Cook, T. H., Smale, S. T., Sakaguchi, S., Livesey, F. J., Fisher, A. G., et al. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20061692 · Cited by 530 · see citing works
Frontline: Neuropilin‐1: a surface marker of regulatory T cells
Bruder, D., Probst-Kepper, M., Westendorf, A., Geffers, R., Beissert, S., Loser, K., von Boehmer, H., Buer, J., & Hansen, W. (2004) · European Journal of Immunology · doi:10.1002/eji.200324799 · Cited by 475 · see citing works
In vivo dynamics of antigen-specific regulatory T cells not predicted from behavior in vitro
Klein, L., Khazaie, K., & von Boehmer, H. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1533365100 · Cited by 375 · see citing works
Role of PTPN22 in type 1 diabetes and other autoimmune diseases
Bottini, N., Vang, T., Cucca, F., & Mustelin, T. (2006) · Seminars in Immunology · doi:10.1016/j.smim.2006.03.008 · Cited by 350 · see citing works
Human regulatory T cells and their role in autoimmune disease
Baecher‐Allan, C., & Hafler, D. A. (2006) · Immunological Reviews · doi:10.1111/j.0105-2896.2006.00417.x · Cited by 270 · see citing works
Identification of Substrates of Human Protein-tyrosine Phosphatase PTPN22
Wu, J., Katrekar, A., Honigberg, L. A., Smith, A. M., Conn, M. T., Tang, J., Jeffery, D. M., Mortara, K. D., Sampang, J., Williams, S. R., et al. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m600498200 · Cited by 240 · see citing works
Chen, C., Rowell, E. A., Thomas, R. M., Hancock, W. W., & Wells, A. D. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m608848200 · Cited by 230 · see citing works
Altered Proliferative Response by T Lymphocytes of Ly-6A (Sca-1) Null Mice
Stanford, W. L., Haque, S., Alexander, R., Liu, X., Latour, A. M., Snodgrass, H. R., Koller, B. H., & Flood, P. M. (1997) · The Journal of Experimental Medicine · doi:10.1084/jem.186.5.705 · Cited by 113 · see citing works
Interfacing T-cell effector and regulatory function through CD137 (4-1BB) co-stimulation
Myers, L. M., & Vella, A. T. (2005) · Trends in Immunology · doi:10.1016/j.it.2005.06.003 · Cited by 75 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
CTLA-4 Control over Foxp3 <sup>+</sup> Regulatory T Cell Function
Wing, K., Onishi, Y., Prieto-Martin, P., Yamaguchi, T., Miyara, M., Fehervari, Z., Nomura, T., & Sakaguchi, S. (2008) · Science · doi:10.1126/science.1160062 · Cited by 2,956 · see citing works
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 · see citing works
Genetic and epigenetic fine mapping of causal autoimmune disease variants
Farh, K. K.-H., Marson, A., Zhu, J., Kleinewietfeld, M., Housley, W. J., Beik, S., Shoresh, N., Whitton, H., Ryan, R. J. H., Shishkin, A. A., et al. (2015) · Nature · doi:10.1038/nature13835 · Cited by 1,956 · see citing works
Self-citationRegulatory T cells in cancer immunotherapy
Tanaka, A., & Sakaguchi, S. (2017) · Cell Research · doi:10.1038/cr.2016.151 · Cited by 1,860 · see citing works
Regulatory T Cell-Derived Interleukin-10 Limits Inflammation at Environmental Interfaces
Rubtsov, Y. P., Rasmussen, J. P., Chi, E. Y., Fontenot, J., Castelli, L., Ye, X., Treuting, P., Siewe, L., Roers, A., Henderson, W. R., et al. (2008) · Immunity · doi:10.1016/j.immuni.2008.02.017 · Cited by 1,586 · see citing works
A census of human transcription factors: function, expression and evolution
Vaquerizas, J. M., Kummerfeld, S. K., Teichmann, S. A., & Luscombe, N. M. (2009) · Nature Reviews Genetics · doi:10.1038/nrg2538 · Cited by 1,573 · see citing works
Koch, M. A., Tucker-Heard, G., Perdue, N. R., Killebrew, J. R., Urdahl, K. B., & Campbell, D. J. (2009) · Nature Immunology · doi:10.1038/ni.1731 · Cited by 1,258 · see citing works
Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control TH2 responses
Zheng, Y., Chaudhry, A., Kas, A., deRoos, P., Kim, J. M., Chu, T.-T., Corcoran, L., Treuting, P., Klein, U., & Rudensky, A. Y. (2009) · Nature · doi:10.1038/nature07674 · Cited by 958 · see citing works
An atlas of combinatorial transcriptional regulation in mouse and man
Ravasi, T., Suzuki, H., Cannistraci, C. V., Katayama, S., Bajic, V. B., Tan, K., Akalin, A., Schmeier, S., Kanamori-Katayama, M., Bertin, N., et al. (2010) · Cell · doi:10.1016/j.cell.2010.01.044 · Cited by 715 · see citing works
Dynamic regulatory network controlling TH17 cell differentiation
Yosef, N., Shalek, A. K., Gaublomme, J. T., Jin, H., Lee, Y., Awasthi, A., Wu, C., Karwacz, K., Xiao, S., Jorgolli, M., et al. (2013) · Nature · doi:10.1038/nature11981 · Cited by 682 · see citing works
The regulation of immune tolerance by FOXP3
Lu, L., Barbi, J., & Pan, F. (2017) · Nature Reviews Immunology · doi:10.1038/nri.2017.75 · Cited by 580 · see citing works
Development and maintenance of intestinal regulatory T cells
Tanoue, T., Atarashi, K., & Honda, K. (2016) · Nature Reviews Immunology · doi:10.1038/nri.2016.36 · Cited by 553 · see citing works
Nylander, A., & Hafler, D. A. (2012) · Journal of Clinical Investigation · doi:10.1172/jci58649 · Cited by 495 · see citing works
T cell receptor signalling networks: branched, diversified and bounded
Brownlie, R. J., & Zamoyska, R. (2013) · Nature Reviews Immunology · doi:10.1038/nri3403 · Cited by 453 · see citing works
Phenotypic analysis of prostate-infiltrating lymphocytes reveals TH17 and Treg skewing
Sfanos, K. S., Bruno, T. C., Maris, C. H., Xu, L., Thoburn, C. J., DeMarzo, A. M., Meeker, A. K., Isaacs, W. B., & Drake, C. G. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-5164 · Cited by 427 · see citing works
Duhen, T., Duhen, R., Lanzavecchia, A., Sallusto, F., & Campbell, D. J. (2012) · Blood · doi:10.1182/blood-2011-11-392324 · Cited by 413 · see citing works
Mechanisms of regulatory T-cell suppression - a diverse arsenal for a moving target
Sojka, D. K., Huang, Y., & Fowell, D. J. (2008) · Immunology · doi:10.1111/j.1365-2567.2008.02813.x · Cited by 393 · see citing works
Immunogenetics of autoimmune thyroid diseases: a comprehensive review
Lee, H. J., Li, C. W., Hammerstad, S. S., Stefan, M., & Tomer, Y. (2015) · Journal of Autoimmunity · doi:10.1016/j.jaut.2015.07.009 · Cited by 351 · see citing works
DuPage, M., Chopra, G., Quiros, J., Rosenthal, W. L., Morar, M. M., Holohan, D., Zhang, R., Turka, L., Marson, A., & Bluestone, J. A. (2015) · Immunity · doi:10.1016/j.immuni.2015.01.007 · Cited by 332 · see citing works
Transcriptional role of cyclin D1 in development revealed by a genetic-proteomic screen
Bienvenu, F., Jirawatnotai, S., Elias, J. E., Meyer, C. A., Mizeracka, K., Marson, A., Frampton, G. M., Cole, M. F., Odom, D. T., Odajima, J., et al. (2010) · Nature · doi:10.1038/nature08684 · Cited by 276 · see citing works
Self-citationFoxp2 regulates gene networks implicated in neurite outgrowth in the developing brain
Vernes, S. C., Oliver, P. L., Spiteri, E., Lockstone, H. E., Puliyadi, R., Taylor, J. M., Ho, J., Mombereau, C., Brewer, A., Lowy, E., et al. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1002145 · Cited by 276 · see citing works
Wells, A. D. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0803917 · Cited by 153 · see citing works
Neuropilin-1: a checkpoint target with unique implications for cancer immunology and immunotherapy
Chuckran, C. A., Liu, C., Bruno, T. C., Workman, C. J., & Vignali, D. A. (2020) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2020-000967 · Cited by 147 · see citing works
A novel function for FOXP3 in humans: intrinsic regulation of conventional T cells
McMurchy, A. N., Gillies, J., Gizzi, M. C., Riba, M., Garcia-Manteiga, J. M., Cittaro, D., Lazarevic, D., Di Nunzio, S., Piras, I. S., Bulfone, A., et al. (2013) · Blood · doi:10.1182/blood-2012-05-431023 · Cited by 77 · see citing works
The Non-Obese Diabetic (NOD) Mouse as a Model of Human Type 1 Diabetes
Kachapati, K., Adams, D., Bednar, K., & Ridgway, W. M. (2012) · Methods in Molecular Biology · doi:10.1007/978-1-62703-068-7_1 · Cited by 54 · see citing works
Kaur, G., Goodall, J. C., Jarvis, L. B., & Hill Gaston, J. S. (2010) · Molecular Immunology · doi:10.1016/j.molimm.2010.07.008 · Cited by 45 · see citing works
Regulatory T Cells: Central Concepts from Ontogeny to Therapy
Khor, B. (2017) · Transfusion Medicine Reviews · doi:10.1016/j.tmrv.2016.07.003 · Cited by 15 · see citing works
Multi-omics analyses reveal novel effects of PLCγ2 deficiency in the mouse brain
Hopp, S. C., Rogers, J. G., Smith, S., Campos, G., Miller, H., Barannikov, S., Kuri, E. G., Wang, H., Han, X., Bieniek, K. F., et al. (2023) · doi:10.1101/2023.12.06.570499 · Cited by 4 · see citing works
“The most relevant over-expressed pathway involves genes with promoters bound by FOXP3, a transcription factor involved in regulatory T-cell function, in stimulated hybridoma cells(28).”
Background
- Authors
- Marson, A., Kretschmer, K., Frampton, G. M., Jacobsen, E. S., Polansky, J. K., MacIsaac, K. D., Levine, S. S., Fraenkel, E., von Boehmer, H., & Young, R. A.
- Affiliations
- Whitehead Institute for Biomedical Research (US)
- Harvard University (US)
- Dana-Farber Cancer Institute (US)
- MIT Computer Science and Artificial Intelligence Laboratory (US)
- Corresponding author
- Young, Richard A.
- ORCID
- Venue
- Nature
- Published
- 2007-01-21
- Volume
- 445
- Issue
- 7130
- Pages
- 931-935
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3008159
- OpenAlex
- W1985406652
- Cited by
- 724
- References
- 33
- Citations by year
- 2026: 11 · 2025: 15 · 2024: 20 · 2023: 18 · 2022: 29 · 2021: 17 · 2020: 24 · 2019: 37 · 2018: 27 · 2017: 31 · 2016: 28 · 2015: 37 · 2014: 46 · 2013: 57 · 2012: 55
- FWCI
- 26.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Site cant be reached (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- National Human Genome Research Institute (R01HG002668)
- National Cancer Institute (P01CA109901)
- 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 › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- Foxp3, regulatory T cells, transcriptional regulation, NFAT, T cell activation, autoimmunity, gene expression inhibition, Treg development, autoimmune disease susceptibility
- MeSH terms
- Animals, Cell Line, Gene Expression Regulation, Lymphocyte Activation, Phenotype, Transcription, Genetic, Models, Immunological, Gene Expression Profiling, T-Lymphocytes, Regulatory, Mice, Forkhead Transcription Factors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
