The DOI matches its Crossref record; 28 of the 28 references it cites were found in a registry or an index.
Analysis of FOXP3 Reveals Multiple Domains Required for Its Function as a Transcriptional Repressor
Open accessAbstract
Foxp3 has been shown to be both necessary and sufficient for the development and function of naturally arising CD4+CD25+ regulatory T cells in mice. Mutation of Foxp3 in Scurfy mice and FOXP3 in humans with IPEX results in fatal, early onset autoimmune disease and demonstrates the critical role of FOXP3 in maintaining immune homeostasis. The FOXP3 protein encodes several functional domains, including a C2H2 zinc finger, a leucine zipper, and a winged-helix/forkhead (FKH) domain. We have shown previously that FOXP3 functions as a transcriptional repressor and inhibits activation-induced IL-2 gene transcription. To characterize the role of each predicted functional domain on the in vivo activity of FOXP3, we have evaluated the location of point mutations identified in a large cohort of patients with the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) and found them to cluster primarily within the FKH domain and the leucine zipper, but also present within the poorly defined N-terminal portion of the protein. The molecular functions of each of the IPEX-targeted domains were investigated. We show that FOXP3 is constitutively localized to the nucleus and this localization requires sequences at both the amino and C-terminal ends of its FKH domain. Moreover, FOXP3 was found to homodimerize through its leucine zipper. We also identify a novel functional domain within the N-terminal half of FOXP3, which is required for FOXP3-mediated repression of transcription from both a constitutively active and a NF-AT-inducible promoter. Furthermore, we demonstrate that IPEX mutations in these domains correlate with deficiencies in FOXP3 repressor function, corroborating their in vivo relevance.
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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
Bennett, C. L., Christie, J., Ramsdell, F., Brunkow, M. E., Ferguson, P. J., Whitesell, L., Kelly, T. E., Saulsbury, F. T., Chance, P. F., & Ochs, H. D. (2001) · Nature Genetics · doi:10.1038/83713 · Cited by 3,402
Self-citationAn 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 2,856
Brunkow, M. E., Jeffery, E. W., Hjerrild, K. A., Paeper, B., Clark, L. B., Yasayko, S.-A., Wilkinson, J. E., Galas, D., Ziegler, S. F., & Ramsdell, F. (2001) · Nature Genetics · doi:10.1038/83784 · Cited by 2,636
Self-citationRegulatory T Cell Lineage Specification by the Forkhead Transcription Factor Foxp3
Fontenot, J. D., Rasmussen, J. P., Williams, L. M., Dooley, J. L., Farr, A. G., & Rudensky, A. Y. (2005) · Immunity · doi:10.1016/j.immuni.2005.01.016 · Cited by 2,279
Wildin, R. S., Ramsdell, F., Peake, J., Faravelli, F., Casanova, J.-L., Buist, N., Levy-Lahad, E., Mazzella, M., Goulet, O., Perroni, L., et al. (2001) · Nature Genetics · doi:10.1038/83707 · Cited by 1,922
Chatila, T. A., Blaeser, F., Ho, N., Lederman, H. M., Voulgaropoulos, C., Helms, C., & Bowcock, A. M. (2000) · Journal of Clinical Investigation · doi:10.1172/jci11679 · Cited by 940
Forkhead Transcription Factors: Key Players in Development and Metabolism
Carlsson, P., & Mahlapuu, M. (2002) · Developmental Biology · doi:10.1006/dbio.2002.0780 · Cited by 840
Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells
Yagi, H., Nomura, T., Nakamura, K., Yamazaki, S., Kitawaki, T., Hori, S., Maeda, M., Onodera, M., Uchiyama, T., Fujii, S., et al. (2004) · International Immunology · doi:10.1093/intimm/dxh165 · Cited by 801
Cited by
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
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
Foxp3 Exploits a Pre-Existent Enhancer Landscape for Regulatory T Cell Lineage Specification
Samstein, R. M., Arvey, A., Josefowicz, S. Z., Peng, X., Reynolds, A., Sandstrom, R., Neph, S., Sabo, P., Kim, J. M., Liao, W., et al. (2012) · Cell · doi:10.1016/j.cell.2012.06.053 · Cited by 472
IPEX syndrome: genetics and treatment options
Ben-Skowronek, I. (2021) · Genes · doi:10.3390/genes12030323 · Cited by 64
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
Metadata
- Authors
- Lopes, J. E., Torgerson, T. R., Schubert, L. A., Anover, S. D., Ocheltree, E. L., Ochs, H. D., & Ziegler, S. F.
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2006-09-01
- Volume
- 177
- Issue
- 5
- Pages
- 3133-3142
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1591129987
- Cited by
- 273
- References
- 28
- FWCI
- 7.68
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Lopes, J. E., Torgerson, T. R., Schubert, L. A., Anover, S. D., Ocheltree, E. L., Ochs, H. D., & Ziegler, S. F. (2006). Analysis of FOXP3 Reveals Multiple Domains Required for Its Function as a Transcriptional Repressor. The Journal of Immunology. https://doi.org/10.4049/jimmunol.177.5.3133
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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