FOXP3 Controls Regulatory T Cell Function through Cooperation with NFAT

  title={FOXP3 Controls Regulatory T Cell Function through Cooperation with NFAT},
  author={Yongqin Wu and Madhuri Borde and Vigo Heissmeyer and Markus Feuerer and Ariya Dararutana Lapan and James C. Stroud and Darren L Bates and Liang Guo and Aidong Han and Steven F. Ziegler and Diane Mathis and Christophe Benoist and Lin Chen and Anjana Rao},

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Inhibition of FOXP3/NFAT Interaction Enhances T Cell Function after TCR Stimulation
In vivo peptide administration of a short synthetic peptide able to inhibit FOXP3/NFAT interaction impaired suppressor activity of conventional Tregs in vitro and suggested that inhibition of NFAT/FOXP3 interaction might improve antitumor immunotherapies.
Regulatory T cells: Perfect partnership
  • S. Ahmad
  • Biology
    Nature Reviews Immunology
  • 2006
NFAT is a common regulator in the immune system, where it can switch transcriptional partners from AP1 to FOXP3, thereby converting the effector T-cell activation programme into the TReg-cell suppressor programme and these findings might have important therapeutic implications.
Foxp3 occupancy and regulation of key target genes during T-cell stimulation
The predominant, although not exclusive, effect of Foxp3 occupancy is to suppress the activation of target genes on T-cell stimulation, which appears to be crucial for the normal function of Treg cells.
FOXP3 Inhibits Activation-Induced NFAT2 Expression in T Cells Thereby Limiting Effector Cytokine Expression1
Using novel cell lines that inducibly express either wild-type or mutant FOXP3, this work has identified NFAT2 as an early target ofFOXP3-mediated transcriptional repression, and demonstrates that transcription from the NFAT1 promoter is significantly suppressed by FOXp3, and NFAT 2 protein expression is markedly diminished in activated CD4+CD25+FOXP3+ TREG compared with CD4-CD25−FOXP 3− T cells.
FOXP 3 Inhibits Activation-Induced NFAT 2 Expression in T Cells Thereby Limiting Effector Cytokine Expression 1
It is shown that FOXP3 functions not only to suppress the first wave of NFAT-mediated transcriptional responses, but may also affect sustained NFat-mediated inflammatory gene expression through suppression of inducible NFAT2 transcription.
FOXP3 Actively Represses Transcription by Recruiting the HAT/HDAC Complex
This work found FOXP3 could actively repress transcription by recruiting distinct histone acetyltransferases and histone deacetylases to function as a corepressor complex and the identification of enzymatic factors operative as essential participants in FoxP3-mediated transcriptional repression provides a practical basis for therapeutically modulating the activity of FOXP 3 in immune suppression.
Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer
A model system is generated for analyzing Foxp3 induction and an enhancer element is identified in this gene, which explains many of the effects of transforming growth factor-β on the function ofFoxp3+ Treg cells.
The Role of FOXP3 in Regulating Immune Responses
The cooperative roles of FOXP3 and other T-cell lineage-defining transcription factors are dissected and it is discussed how these networks not only control the ability to Tregs to suppress different types of immune responses, but also enable Treg plasticity.
Revisiting the Concept of Targeting NFAT to Control T Cell Immunity and Autoimmune Diseases
The nuclear factor of activated T cells (NFAT) family of transcription factors, which includes NFAT1, NFAT2, and NFAT4, are well-known to play important roles in T cell activation. Most of NFAT
Chapter 2 FoxP 3 and Regulatory T Cells
Retinoic acid may interfere with the negative impact of costimulation on Treg conversion by interfering with the generation and/or function of AP-1, which appears to interfere with a Foxp3-NFAT transcription complex.


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.
It is demonstrated 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.
Scurfin (FOXP3) Acts as a Repressor of Transcription and Regulates T Cell Activation*
The 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.
Control of Regulatory T Cell Development by the Transcription Factor Foxp3
Foxp3, which encodes a transcription factor that is genetically defective in an autoimmune and inflammatory syndrome in humans and mice, is specifically expressed in naturally arising CD4+ regulatory T cells and retroviral gene transfer of Foxp3 converts naïve T cells toward a regulatory T cell phenotype similar to that of naturally occurring CD4+.
Transcription factors of the NFAT family: regulation and function.
Recent data on the diversity of the NFAT family of transcription factors, the regulation of NFAT proteins within cells, and the cooperation ofNFAT proteins with other transcription factors to regulate the expression of inducible genes are discussed.
Mechanisms of transactivation by nuclear factor of activated T cells-1
The results emphasize the multiple levels at whichNFAT- dependent transactivation is regulated, and predict significant differences in the architecture of cooperative transcription complexes containing different NFAT-family proteins.
TH cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes
The data point to a biphasic process in which cytokine-driven signaling pathways maintain and reinforce chromatin structural changes initiated by the TCR, which ensures that cytokine genes remain accessible to the relevant transcription factors and promotes functional cooperation of the inducible transcription factor NFAT with lineage-specific transcription factors such as GATA-3 and T-bet.
NFATc2 and NFATc3 transcription factors play a crucial role in suppression of CD4+ T lymphocytes by CD4+ CD25+ regulatory T cells
Combined NFATc2/c3 deficiency is compatible with the development of CD4+ CD25+ T reg cells but renders conventionalCD4+ T cells unresponsive to suppression, underlining the importance of NFAT proteins for sustaining T cell homeostasis.
A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3
Principal advances in the understanding of the molecular mechanisms of Treg cell development and function are discussed with particular emphasis on the forkhead transcription factor Foxp3.
Murine CD4+CD25+ Regulatory T Cells Fail to Undergo Chromatin Remodeling Across the Proximal Promoter Region of the IL-2 Gene1
Using a PCR-based chromatin accessibility assay, it was found that the minimal IL-2 promoter region of CD4+CD25+ Treg cells, unlike conventional CD4 T cells, did not undergo chromatin remodeling following stimulation, suggesting that the inability of the Treg Cells to secrete IL- 2 following activation is controlled at the chromatin level.