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. 2005 Apr 5;102(14):5138-43. doi: 10.1073/pnas.0501675102.
- 1. Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
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.