The nuclear orphan receptor Nr4a2 induces Foxp3 and regulates differentiation of CD4+ T cells.
The nuclear orphan receptor Nr4a2 induces Foxp3 and regulates differentiation of CD4+ T cells.
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DOI：
10.1038/ncomms1272
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发表时间：
2011
影响因子：
16.6
通讯作者：
Yoshimura, Akihiko
中科院分区：
文献类型：
--
作者：
Sekiya, Takashi;Kashiwagi, Ikkou;Inoue, Naoko;Morita, Rimpei;Hori, Shohei;Waldmann, Herman;Rudensky, Alexander Y.;Ichinose, Hiroshi;Metzger, Daniel;Chambon, Pierre;Yoshimura, Akihiko
调节性T细胞(Treg)通过多种机制在维持免疫动态平衡方面发挥重要作用。虽然Forkhead转录因子Foxp3定义了Treg细胞的谱系和功能，但Foxp3诱导和维持的分子机制仍然不清楚。在这里，我们表明Foxp3是Nr4a2的直接靶标之一。Nr4a2与Foxp3的调节区结合，在那里它介导允许的组蛋白修饰。Nr4a2的异位表达通过诱导Foxp3和抑制细胞因子的产生，包括干扰素-γ和白介素2，赋予幼稚的CD_4+T细胞Treg样的抑制活性。T细胞中Nr4a2的缺失会减弱Tregs的诱导，并导致Th1的异常诱导，从而导致结肠炎的恶化。Nr4a2缺陷树突状细胞在体外和体内都容易失去Foxp3的表达，并具有减弱的抑制能力。因此，Nr4a2通过调节Tregs的诱导、维持和抑制功能，以及通过抑制异常的Th1诱导，具有维持T细胞稳态的能力。调节性T细胞的特征是Foxp3的表达，然而，该蛋白的表达如何受到控制尚不清楚。在这里，作者证明了核孤儿受体Nr4a2是Foxp3的转录激活因子，并提示它是调节性T细胞功能所必需的。
Regulatory T cells (Tregs) have a central role in maintaining immune homoeostasis through various mechanisms. Although the Forkhead transcription factor Foxp3 defines the Treg cell lineage and functions, the molecular mechanisms of Foxp3 induction and maintenance remain elusive. Here we show that Foxp3 is one of the direct targets of Nr4a2. Nr4a2 binds to regulatory regions of Foxp3, where it mediates permissive histone modifications. Ectopic expression of Nr4a2 imparts Treg-like suppressive activity to naïve CD4+ T cells by inducing Foxp3 and by repressing cytokine production, including interferon-γ and interleukin-2. Deletion of Nr4a2 in T cells attenuates induction of Tregs and causes aberrant induction of Th1, leading to the exacerbation of colitis. Nr4a2-deficeint Tregs are prone to lose Foxp3 expression and have attenuated suppressive ability both in vitro and in vivo. Thus, Nr4a2 has the ability to maintain T-cell homoeostasis by regulating induction, maintenance and suppressor functions of Tregs, and by repression of aberrant Th1 induction. Regulatory T cells are characterized by the expression of Foxp3, however, how the expression of this protein is controlled is unclear. Here, the authors show that the nuclear orphan receptor, Nr4a2, is a transcriptional activator of Foxp3, and suggest that it is required for the function of regulatory T cells.
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影响因子：
32.4
作者：
Hill, Jonathan A.;Feuerer, Markus;Benoist, Christophe
通讯作者：
Benoist, Christophe
影响因子：
11.4
作者：
Cheng, LEC;Chan, FKM;Winoto, A
通讯作者：
Winoto, A
影响因子：
30.8
作者：
Le, WD;Xu, PY;Vassilatis, DK
通讯作者：
Vassilatis, DK
DOI：
10.1073/pnas.0811556106
发表时间：
2009-02-10
影响因子：
11.1
作者：
Komatsu, Noriko;Mariotti-Ferrandiz, Maria Encarnita;Hori, Shohei
通讯作者：
Hori, Shohei
影响因子：
64.8
作者：
Ono, Masahiro;Yaguchi, Hiroko;Sakaguchi, Shimon
通讯作者：
Sakaguchi, Shimon