FOXP3 controls regulatory T cell function through cooperation with NFAT.
By Yongqing Wu, M. Borde, V. Heissmeyer, M. Feuerer, A. Lapan, J. Stroud, D. Bates, Liang Guo, A. Han, Steven F. Ziegler and 4 more. Cell, 2006
1,254 citations recorded by the source corpus.
Antigen stimulation of immune cells activates the transcription factor NFAT, a key regulator of T cell activation and anergy. NFAT forms cooperative complexes with the AP-1 family of transcription factors and regulates T cell activation-associated genes. Here we show that regulatory T cell (Treg) function is mediated by an analogous cooperative complex of NFAT with the forkhead transcription factor FOXP3, a lineage specification factor for Tregs. The crystal structure of an NFAT:FOXP2:DNA complex reveals an extensive protein-protein interaction interface between NFAT and FOXP2. Structure-guided mutations of FOXP3, predicted to progressively disrupt its interaction with NFAT, interfere in a graded manner with the ability of FOXP3 to repress expression of the cytokine IL2, upregulate expression of the Treg markers CTLA4 and CD25, and confer suppressor function in a murine model of autoimmune diabetes. Thus by switching transcriptional partners, NFAT converts the acute T cell activation program into the suppressor program of Tregs.
Subfields: Immunology, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/d0eb562347ebf75181c5fc494c2d7a229d9f0f5e
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Citations in the corpus
- Dual functions for the endoplasmic reticulum calcium sensors STIM1 and STIM2 in T cell activation and tolerance (2008, background): “and a requirement for NFAT in Foxp3-mediated transcription and suppressor functio”
- CREB/ATF-dependent T cell receptor–induced FoxP3 gene expression: a role for DNA methylation (2007, background): “FoxP3 can interact with NF-AT and NF-κB to repress cytokine gene expression (4, 5).”
- Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. (2007, background): “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).”
- The development of inflammatory TH-17 cells requires interferon-regulatory factor 4 (2007, background): “Foxp3 is not only a marker for regulatory T cells but also can suppress the functions of other transcription factors such as NFA”
- Foxp3 in control of the regulatory T cell lineage (2007, background): “The resulting mutant Foxp3 protein lacking in ability to bind NFAT failed to promote acquisition of suppressor function and T reg cell–like surface properties upon expression in activated nonregulatory T cell”
- Peripheral CD4 T cell differentiation regulated by networks of cytokines and transcription factors (2010, background): “Tone Y, Furuuchi K, Kojima Y, Tykocinski ML, Greene MI, Tone M. Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer.”
- Regulatory T cells and immune tolerance. (2008, background): “Foxp3 - dependent and - independent molecules specific for CD25 + CD4 + natural regulatory T cells revealed by DNA microar Szanya , V .”