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.

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.

• Authors: Estelle Bettelli, Maryam Dastrange, Mohamed Oukka
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 102 Issue 14 Pg. 5138-43 (Apr 05 2005) ISSN: 0027-8424 [Print] United States
• PMID: 15790681 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cytokines
• DNA-Binding Proteins
• FOXP3 protein, human
• Forkhead Transcription Factors
• Foxp3 protein, mouse
• Interleukin-2
• NF-kappa B
• NFATC Transcription Factors
• Nuclear Proteins
• Repressor Proteins
• Transcription Factors
• Interleukin-4
• Interferon-gamma

Topics

• Animals
• Autoimmunity
• Cell Line
• Cytokines (biosynthesis, genetics)
• DNA-Binding Proteins (deficiency, genetics, metabolism)
• Down-Regulation
• Forkhead Transcription Factors
• Gene Expression
• Humans
• Interferon-gamma (biosynthesis, genetics)
• Interleukin-2 (biosynthesis, genetics)
• Interleukin-4 (biosynthesis, genetics)
• Jurkat Cells
• Mice
• Mice, Knockout
• Mice, Transgenic
• NF-kappa B (metabolism)
• NFATC Transcription Factors
• Nuclear Proteins (metabolism)
• Repressor Proteins (genetics, metabolism)
• T-Lymphocytes, Helper-Inducer (immunology, metabolism)
• Transcription Factors (metabolism)
• Transcriptional Activation