Scurfin (FOXP3) Acts as a Repressor of Transcription and Regulates T Cell Activation*

By Lisa A. Schubert, E. Jeffery, Yi Zhang, F. Ramsdell, Steven F. Ziegler. Journal of Biological Chemistry, 2001

595 citations recorded by the source corpus.

We have recently identified and clonedFoxp3, the gene defective in mice with thescurfy mutation. The immune dysregulation documented in these mice and in humans with mutations in the orthologous gene indicates that the foxp3 gene product, scurfin, is involved in the regulation of T cell activation and differentiation. The autoimmune state observed in these patients with the immune dysregulation polyendocrinopathy, enteropathy, X-linked syndrome, or X-linked autoimmunity-allergic dysregulation syndrome also points to a critical role for scurfin in the regulation of T cell homeostasis.FOXP3 encodes a novel member of the forkhead family of transcription factors. Here we demonstrate that this structural domain is required for nuclear localization and DNA binding. Scurfin, transiently expressed in heterologous cells, represses transcription of a reporter containing a multimeric forkhead binding site. Upon overexpression in CD4 T cells, scurfin attenuates activation-induced cytokine production and proliferation. We have identified FKH binding sequences adjacent to critical NFAT regulatory sites in the promoters of several cytokine genes whose expression is sensitive to changes in SFN abundance. Our findings indicate that the ability of scurfin to bind DNA, and presumably repress transcription, plays a paramount role in determining the amplitude of the response of CD4 T cells to activation.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/6794cbca3fbaa57b24c0df7c09282171daacb632

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Citations in the corpus

Regulatory T cells and mechanisms of immune system control (2004, background): “Foxp3 has been suggested to act as a negative modulator of IL-2 transcriptio”
Cutting Edge: Direct Suppression of B Cells by CD4+CD25+ Regulatory T Cells1 (2005, background): “Foxp3 is a transcriptional repressor (20) mutated in scurfy mice that lack conventional CD4 CD25 Tregs (21) and in human immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome patients with autoimmune diseases (22).”
Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. (2007, methodology): “Expression of FOXP3 in Teff cells does not negatively regulate cytokine production nTregs fail to produce significant amounts of most cytokines, likely due to the ability of FOXP3 to physically interact with and repress transcription from cytokine promoters (7, 17 , 24, 25).”
Foxp3 programs the development and function of CD4+CD25+ regulatory T cells (2003, background): “Notably, heterozygous female Foxp3 +/sf carriers display random X chromosome inactivation, yet do not develop lymphoproliferative autoimmunit”
FOXP3 controls regulatory T cell function through cooperation with NFAT. (2006, unknown): “Thus FOXP3 represses NFAT:AP-1 activity, not by displacing NFAT from NFAT:AP-1 composite sites as suggested previously (Schubert et al., 2001), but rather by forming a cooperative NFAT:FOXP3:DNA complex that re-sembles the cooperative NFAT:Fos:Jun:DNA complex.”
Regulatory T cells in tumor microenvironment: new mechanisms, potential therapeutic strategies and future prospects (2020, background): “Foxp3 may act as a repressor of transcription upon activation [24].”
The PD-1 Pathway in Tolerance and Autoimmunity (2010, background): “Scurfin was later found to be the transcription factor, Foxp3 (67, 82).”
PD-L1 regulates the development, maintenance, and function of induced regulatory T cells (2009, background): “PD-L1/PD-L2/Rag/ recipients of Foxp3 naive T cells resemble scurfy mice, which have a deficit in Foxp3 and die by 3 wk of age as a result of multiorgan infiltration of CD4+CD8 T cells (Clark et al., 1999; Brunkow et al., 2001; Schubert et al., 2001).”
A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3 (2005, background): “Foxp3 binds DNA, localizes to the nucleus and can act as a transcriptional represso”
Antigen-dependent Proliferation of CD4+ CD25+ Regulatory T Cells In Vivo (2003, background): “It is intriguing to speculate that this might be associated with the preferential expression of the transcription factor Foxp3 in CD25 Tregs (16, 17) that has been shown to inhibit transcription of IL-2 in a Jurkat transfection system (18).”
IL-10-Secreting Regulatory T Cells Do Not Express Foxp3 but Have Comparable Regulatory Function to Naturally Occurring CD4+CD25+ Regulatory T Cells 1 (2004, background): “Foxp3 was suggested to act as a negative modulator of IL-2 transcription (32).”