Tone, Y., Furuuchi, K., Kojima, Y., Tykocinski, M.L., Greene, M.I. & Tone, M 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: 20). 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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    ABSTRACT: The β-galactoside-binding protein galectin-9 is critical in regulating the immune response, but the mechanism by which it functions remains unclear. We have demonstrated that galectin-9 is highly expressed by induced regulatory T cells (iTreg) and was crucial for the generation and function of iTreg cells, but not natural regulatory T (nTreg) cells. Galectin-9 expression within iTreg cells was driven by the transcription factor Smad3, forming a feed-forward loop, which further promoted Foxp3 expression. Galectin-9 increased iTreg cell stability and function by directly binding to its receptor CD44, which formed a complex with transforming growth factor-β (TGF-β) receptor I (TGF-βRI), and activated Smad3. Galectin-9 signaling was further found to regulate iTreg cell induction by dominantly acting through the CNS1 region of the Foxp3 locus. Our data suggest that exogenous galectin-9, in addition to being an effector molecule for Treg cells, acts synergistically with TGF-β to enforce iTreg cell differentiation and maintenance.
    Immunity 07/2014; 41(2). DOI:10.1016/j.immuni.2014.06.011 · 21.56 Impact Factor
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    • "CNS1, an intronic enhancer (enhancer 1), contains the TGF-β-responsive elements, that is, the Smad2/3 binding sites, close to the NFAT site. These elements are essential for TGF-β-induced Foxp3 expression in iTreg cells [25, 26]. Genetic deletion of CNS1 in mice revealed that CNS1 is redundant for nTreg cell differentiation, but essential for iTreg cell generation in gut-associated lymphoid tissues [27]. "
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    ABSTRACT: Several reports have suggested that natural regulatory T cells (Tregs) lose Forkhead box P3 (Foxp3) expression and suppression activity under certain inflammatory conditions. Treg plasticity has been studied because it may be associated with the pathogenesis of autoimmunity. Some studies showed that a minor uncommitted Foxp3(+) T cell population, which lacks hypomethylation at Treg-specific demethylation regions (TSDRs), may convert to effector/helper T cells. Suppressor of cytokine signaling 1 (SOCS1), a negative regulator of cytokine signaling, has been reported to play an important role in Treg cell integrity and function by protecting the cells from excessive inflammatory cytokines. In this review, we discuss Treg plasticity and maintenance of suppression functions in both physiological and pathological settings. In addition, we discuss molecular mechanisms of maintaining Treg plasticity by SOCS1 and other molecules. Such information will be useful for therapy of autoimmune diseases and reinforcement of antitumor immunity.
    Research Journal of Immunology 07/2014; 2014:943149. DOI:10.1155/2014/943149
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    • "It has been reported that Nfat proteins are required to generate functional Tregs, as they interact with Foxp3 and other Treg-specific or Treg-selective factors that regulate expression of IL-2, CD25, CTLA-4, and Foxp3 itself [5], [7], [10], [36]. However, recent data have challenged the requirement for Nfatc2 to support Treg function [15], and suggested it is the combined threshold of Nfat proteins (all isoforms), which regulates Foxp3 expression and generation of iTregs [16]. "
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    ABSTRACT: Nfatc2 and Tob1 are intrinsic negative regulators of T cell activation. Nfatc2-deficient and Tob1-deficient T cells show reduced thresholds of activation; however, whether these factors have independent or overlapping roles in negative regulation of T cell responses has not been previously examined. Here, we show that Nfatc2 knockout (KO) but not Tob1 KO mice have age-associated accumulation of persistently activated T cells in vivo and expansion of the CD44+ memory cell compartment and age-associated lymphocytic infiltrates in visceral organs, without significant changes in numbers of CD4+CD25+Foxp3+ regulatory T cells (Treg). In vitro, CD4+CD25- "conventional" T cells (Tconvs) from both KO strains showed greater proliferation than wild type (WT) Tconvs. However, while Tregs from Nfatc2 KO mice retained normal suppressive function, Tregs from Tob1 KOs had enhanced suppressive activity. Nfatc2 KO Tconvs expanded somewhat more rapidly than WT Tconvs under conditions of homeostatic proliferation, but their accelerated growth capacity was negated, at least acutely, in a lymphoreplete environment. Finally, Nfatc2 KO mice developed a previously uncharacterized increase in B-cell malignancies, which was not accelerated by the absence of Tob1. The data thus support the prevailing hypothesis that Nfatc2 and Tob1 are non-redundant regulators of lymphocyte homeostasis.
    PLoS ONE 06/2014; 9(6):e100629. DOI:10.1371/journal.pone.0100629 · 3.23 Impact Factor
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