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.
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.
Mesh Terms:
Animals, Autoimmunity, Cell Line, Cytokines, DNA-Binding Proteins, Down-Regulation, Forkhead Transcription Factors, Gene Expression, Humans, Interferon-gamma, Interleukin-2, Interleukin-4, Jurkat Cells, Mice, Mice, Knockout, Mice, Transgenic, NF-kappa B, NFATC Transcription Factors, Nuclear Proteins, Repressor Proteins, T-Lymphocytes, Helper-Inducer, Transcription Factors, Transcriptional Activation
Animals, Autoimmunity, Cell Line, Cytokines, DNA-Binding Proteins, Down-Regulation, Forkhead Transcription Factors, Gene Expression, Humans, Interferon-gamma, Interleukin-2, Interleukin-4, Jurkat Cells, Mice, Mice, Knockout, Mice, Transgenic, NF-kappa B, NFATC Transcription Factors, Nuclear Proteins, Repressor Proteins, T-Lymphocytes, Helper-Inducer, Transcription Factors, Transcriptional Activation
Proc. Natl. Acad. Sci. U.S.A.
Date: Apr. 05, 2005
PubMed ID: 15790681
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