Foxp3 interacts with nuclear factor of activated T cells and NF-κB to repress cytokine gene expression and effector functions of T helper cells
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- Estelle Bettelli
- Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115; and Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, 65 Lansdowne Street, Cambridge, MA 02139
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- Maryam Dastrange
- Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115; and Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, 65 Lansdowne Street, Cambridge, MA 02139
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- Mohamed Oukka
- Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115; and Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, 65 Lansdowne Street, Cambridge, MA 02139
Abstract
<jats:p>Scurfy mice, which are deficient in a functional Foxp3, exhibit a severe lymphoproliferative disorder and display generalized over-production of cytokines. Here, we show that, among the Foxp transcriptional factor family, which includes Foxp1, Foxp2, and Foxp3, only Foxp3 has the ability to inhibit IL-2, IL-4, and IFN-γ production by primary T helper cells. We found that Foxp3 physically associates with the Rel family transcription factors, nuclear factor of activated T cells (NFAT) and NF-κB, and blocks their ability to induce the endogenous expression of their target genes, including key cytokine genes. More importantly, T cells derived from scurfy mice have a dramatic increase in nuclear factor of activated T cells (NFAT) and NF-κB transcriptional activity compared with the T cells derived from WT mice. Furthermore, complementation of Foxp3 in scurfy-derived T cells lowers the NFAT and NF-κB transcriptional activity to the physiological level. Finally, we show that myelin proteolipid protein-specific autoreactive T cells transduced with Foxp3 cannot mediate experimental autoimmune encephalomyelitis, providing further support that Foxp3 suppresses the effector function of autoreactive T cells. Foxp3 has already been associated with the generation of CD4<jats:sup>+</jats:sup>CD25<jats:sup>+</jats:sup>regulatory T cells; our data additionally demonstrate that Foxp3 suppresses the effector functions of T helper cells by directly inhibiting the activity of two key transcription factors, NFAT and NF-κB, which are essential for cytokine gene expression and T cell functions.</jats:p>
Journal
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 102 (14), 5138-5143, 2005-03-24
Proceedings of the National Academy of Sciences
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Keywords
Details 詳細情報について
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- CRID
- 1362825896011084288
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- NII Article ID
- 80017352872
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- ISSN
- 10916490
- 00278424
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- Data Source
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- Crossref
- CiNii Articles