GATA3-driven Th2 responses inhibit TGF-beta1-induced FOXP3 expression and the formation of regulatory T cells.
GATA3-driven Th2 responses inhibit TGF-beta1-induced FOXP3 expression and the formation of regulatory T cells.
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GATA3驱动的Th2响应抑制TGF-BETA1诱导的FOXP3表达和调节T细胞的形成。
DOI：
10.1371/journal.pbio.0050329
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发表时间：
2007-12
期刊：
影响因子：
9.8
通讯作者：
Schmidt-Weber CB
中科院分区：
文献类型：
--
作者：
Mantel PY;Kuipers H;Boyman O;Rhyner C;Ouaked N;Rückert B;Karagiannidis C;Lambrecht BN;Hendriks RW;Crameri R;Akdis CA;Blaser K;Schmidt-Weber CB
转录因子协同作用以诱导向Th1、Th2或T调节（Treg）细胞的谱系定型，并且它们的反调节机制被证明对于Th1和Th2表型之间的极化至关重要。FOXP3是天然的、胸腺衍生的（nTreg）和诱导性Treg（iTreg）定型的必需转录因子;然而，调节其表达的机制尚不清楚。我们描述了一种控制iTreg极化的机制，该机制被Th2分化途径所推翻。我们证明，白细胞介素4（IL-4）在T细胞启动时抑制FOXP3。这种抑制机制也在Th2细胞和在T细胞中过表达加塔-3的转基因小鼠的T细胞中得到证实，所述T细胞显示在转化生长因子（TGF）-β-介导的FOXP3诱导中缺乏。这种抑制作用是通过GATA 3与FOXP 3启动子的直接结合介导的，从而抑制其反式激活过程。因此，这项研究提供了一个新的理解耐受性的发展，由2型免疫反应控制。小鼠中的IL-4治疗降低了iTreg细胞频率，这突出表明靶向IL-4或GATA 3的治疗方法可能提供新的预防策略，促进耐受性诱导，特别是在Th2介导的疾病中，如过敏。针对外来或自体抗原的特异性免疫应答由特化的表位特异性T细胞驱动，其数量在识别在专职抗原呈递细胞上发现的抗原后扩大。随后的成熟过程涉及某些T细胞表型的分化，例如促炎细胞（Th1，Th2，Th17）或调节性T（Treg）细胞，其用于保持免疫应答受到检查。目前的研究集中在两个关键的转录因子FOXP3和GATA 3在控制这些细胞的承诺的作用。我们证明了Th2细胞因子IL-4抑制FOXP3的诱导，从而抑制诱导型Treg细胞的产生。我们发现IL-4诱导的GATA 3通过直接结合FOXP 3启动子中的加塔元件介导FOXP 3抑制。我们假设，旨在中和IL-4的治疗剂可能是一种新的策略，以促进诱导型Treg细胞的产生，从而促进过敏和其他Th2主导的疾病的耐受性。结果表明，Th2应答阻止诱导型Tcl3的产生。这是由IL-4诱导GATA 3介导的，GATA 3直接结合并抑制FOXP 3启动子。这种机制可能与诱导免疫耐受有关，特别是在过敏性疾病中。
Transcription factors act in concert to induce lineage commitment towards Th1, Th2, or T regulatory (Treg) cells, and their counter-regulatory mechanisms were shown to be critical for polarization between Th1 and Th2 phenotypes. FOXP3 is an essential transcription factor for natural, thymus-derived (nTreg) and inducible Treg (iTreg) commitment; however, the mechanisms regulating its expression are as yet unknown. We describe a mechanism controlling iTreg polarization, which is overruled by the Th2 differentiation pathway. We demonstrated that interleukin 4 (IL-4) present at the time of T cell priming inhibits FOXP3. This inhibitory mechanism was also confirmed in Th2 cells and in T cells of transgenic mice overexpressing GATA-3 in T cells, which are shown to be deficient in transforming growth factor (TGF)-β–mediated FOXP3 induction. This inhibition is mediated by direct binding of GATA3 to the FOXP3 promoter, which represses its transactivation process. Therefore, this study provides a new understanding of tolerance development, controlled by a type 2 immune response. IL-4 treatment in mice reduces iTreg cell frequency, highlighting that therapeutic approaches that target IL-4 or GATA3 might provide new preventive strategies facilitating tolerance induction particularly in Th2-mediated diseases, such as allergy. Specific immune responses against foreign or autologous antigens are driven by specialized epitope-specific T cells, whose numbers expand upon recognition of antigen found on professional antigen-presenting cells. The subsequent maturation process involves the differentiation of certain T cell phenotypes such as pro-inflammatory cells (Th1, Th2, Th17) or regulatory T (Treg) cells, which serve to keep the immune response in check. The current study focuses on the role of two key transcription factors—FOXP3 and GATA3—in controlling the commitment of these cells. We demonstrate that the Th2 cytokine IL-4 inhibits the induction of FOXP3 and thus inhibits the generation of inducible Treg cells. We show that IL-4–induced GATA3 mediates FOXP3 inhibition by directly binding to a GATA element in the FOXP3 promoter. We hypothesize that therapeutic agents aimed at neutralizing IL-4 could be a novel strategy to facilitate inducible Treg cell generation and thus promotion of tolerance in allergies and other Th2-dominated diseases. It is shown that Th2 responses prevent the generation of inducible Tregs. This is mediated by IL-4 induction of GATA3, which binds directly to and represses the FOXP3 promoter. This mechanism is likely to be relevant in the induction of immunotolerance, particularly in allergic diseases.
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影响因子：
64.8
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
通讯作者：
Kuchroo, VK
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影响因子：
15.3
作者：
Finotto, S;De Sanctis, G T;Lehr, H A;Herz, U;Buerke, M;Schipp, M;Bartsch, B;Atreya, R;Schmitt, E;Galle, P R;Renz, H;Neurath, M F
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Neurath, M F
影响因子：
56.9
作者：
Hwang, ES;Szabo, SJ;Glimcher, LH
通讯作者：
Glimcher, LH
影响因子：
2.2
作者：
Lutz, MB;Kukutsch, N;Schuler, G
通讯作者：
Schuler, G
影响因子：
4.4
作者：
Gorelik, L;Fields, PE;Flavell, RA
通讯作者：
Flavell, RA