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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Bettelli, Estelle Dastrange, Maryam Oukka, Mohamed |
| Description | Author Affiliation: Bettelli E ( Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.); |
| Abstract | 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-gamma 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-kappaB, 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-kappa B 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-kappa B 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(+)CD25+ 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-kappa B, which are essential for cytokine gene expression and T cell functions. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 14 |
| Volume Number | 102 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2005-04-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Cytokines Genetics DNA-Binding Proteins Metabolism NF-kappa B Nuclear Proteins T-Lymphocytes, Helper-Inducer Immunology Transcription Factors Animals Autoimmunity Cell Line Biosynthesis Deficiency Down-Regulation Forkhead Transcription Factors Gene Expression Interferon-gamma Interleukin-2 Interleukin-4 Jurkat Cells Mice Mice, Knockout Mice, Transgenic NFATC Transcription Factors Repressor Proteins Transcriptional Activation Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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