Article

Tone, Y. et al. Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer. Nat. Immunol. 9, 194-202

Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Nature Immunology (Impact Factor: 24.97). 03/2008; 9(2):194-202. DOI: 10.1038/ni1549
Source: PubMed

ABSTRACT The transcription factor Foxp3 is involved in the differentiation, function and survival of CD4+CD25+ regulatory T (T(reg)) cells. Details of the mechanism underlying the induction of Foxp3 expression remain unknown, because studies of the transcriptional regulation of the Foxp3 gene are limited by the small number of T(reg) cells in mononuclear cell populations. Here we have generated a model system for analyzing Foxp3 induction and, by using this system with primary T cells, we have identified an enhancer element in this gene. The transcription factors Smad3 and NFAT are required for activity of this Foxp3 enhancer, and both factors are essential for histone acetylation in the enhancer region and induction of Foxp3. These biochemical properties that define Foxp3 expression explain many of the effects of transforming growth factor-beta on the function of Foxp3+ T(reg) cells.

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Available from: Yukiko Tone, Apr 15, 2014
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    • "Unexpectedly, the Foxp3 promoter region contains few TGF-b-responsive elements and therefore has only limited influence on the induction of Foxp3 upon TGF-b stimulation . Instead, the intronic enhancer I (CNS1) region, which contains both NFAT and Smad3 binding sites, was determined to be the more dominant regulatory site and largely controls the expression of Foxp3 following TGF-b signaling (Tone et al., 2008; Xu et al., 2010). It has been described that CNS1-deficient mice exhibit dysregulated immune response on the mucosal surface , due to the iTreg cell deficiency, while Th1 and Th17 cells are not altered (Josefowicz et al., 2012b; Katoh et al., 2007). "
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    • "Smad2 and Smad3 are collectively essential for the activation of the FoxP3 expression during iTreg cell conversion via their direct binding to a foxp3 CNS1 (Takimoto et al., 2010; Tone et al., 2008). To test whether the attenuated Smad phosphorylation observed in GILZ-deficient T cells results in their compromised transcriptional activity, we performed chromatin immunoprecipitation (ChIP) assays using CD4 + CD25 À T cells purified from WT and gilz cKO mice and activated in vitro in the presence of TGF-b. "
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    • "The redundant function of different NF-AT isoforms expressed in T lineage cells has made it difficult to ascertain the role of this group of transcription factors in tTreg development. NF-AT is required for the induction of Foxp3 transcription in vitro [26] [27]. However, thymic regulatory T cell development and function are relatively normal in NF-ATc1/NF-ATc4 double deficient mice [28], with the suggestion that NF-ATc2 may compensate for the lack of NF-ATc1 and NF-ATc4 in these animals. "
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