PMID:15790681

Citation	Bettelli, E, Dastrange, M and Oukka, M (2005) Foxp3 interacts with nuclear factor of activated T cells and NF-kappa B to repress cytokine gene expression and effector functions of T helper cells. Proc. Natl. Acad. Sci. U.S.A. 102:5138-43
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.
Links	PubMed PMC555574 Online version:10.1073/pnas.0501675102
Keywords	Animals; Autoimmunity; Cell Line; Cytokines/biosynthesis; Cytokines/genetics; DNA-Binding Proteins/deficiency; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Down-Regulation; Forkhead Transcription Factors; Gene Expression; Humans; Interferon-gamma/biosynthesis; Interferon-gamma/genetics; Interleukin-2/biosynthesis; Interleukin-2/genetics; Interleukin-4/biosynthesis; Interleukin-4/genetics; Jurkat Cells; Mice; Mice, Knockout; Mice, Transgenic; NF-kappa B/metabolism; NFATC Transcription Factors; Nuclear Proteins/metabolism; Repressor Proteins/genetics; Repressor Proteins/metabolism; T-Lymphocytes, Helper-Inducer/immunology; T-Lymphocytes, Helper-Inducer/metabolism; Transcription Factors/metabolism; Transcriptional Activation
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