The nuclear receptor PPAR gamma selectively inhibits Th17 differentiation in a T cell-intrinsic fashion and suppresses CNS autoimmunity.
The nuclear receptor PPAR gamma selectively inhibits Th17 differentiation in a T cell-intrinsic fashion and suppresses CNS autoimmunity.
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DOI：
10.1084/jem.20082771
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发表时间：
2009-09-28
期刊：
影响因子：
--
通讯作者：
Knolle PA
中科院分区：
文献类型：
--
作者：
Klotz L;Burgdorf S;Dani I;Saijo K;Flossdorf J;Hucke S;Alferink J;Nowak N;Beyer M;Mayer G;Langhans B;Klockgether T;Waisman A;Eberl G;Schultze J;Famulok M;Kolanus W;Glass C;Kurts C;Knolle PA
分泌白细胞介素(IL)-17 （Th17细胞）的T辅助细胞在多发性硬化症（MS）等自身免疫性疾病中起着至关重要的作用。Th17分化由转化生长因子(TGF)-β/IL-6或IL-21联合诱导，需要转录因子视黄酸受体相关孤儿受体γt （RORγt）的表达。我们发现核受体过氧化物酶体增殖激活受体γ (PPARγ)是人类和小鼠Th17分化的关键负调控因子。CD4+ T细胞中的PPARγ活化选择性地抑制Th17分化，但不分化为Th1、Th2或调节性T细胞。PPARγ通过抑制TGF-β/ il -6诱导的T细胞中RORγt的表达来控制Th17的分化。在T细胞中，PPARγ的药理激活阻止了类视黄醇和甲状腺激素受体协同抑制因子的沉默介质从RORγt启动子中移除，从而干扰了RORγt转录。T细胞特异性PPARγ敲除和内源性配体激活均揭示了PPARγ在T细胞持续内在控制Th17分化和自身免疫发展中的生理作用。重要的是，来自健康对照和MS患者的CD4+ T细胞对ppar γ介导的Th17分化抑制非常敏感。总之，我们报道了ppar γ介导的T细胞内在分子机制，该机制选择性地控制小鼠和人类的Th17分化，并可接受药物调节。因此，我们认为PPARγ代表了th17介导的自身免疫性疾病（如MS）特异性免疫干预的一个有希望的分子靶点。
T helper cells secreting interleukin (IL)-17 (Th17 cells) play a crucial role in autoimmune diseases like multiple sclerosis (MS). Th17 differentiation, which is induced by a combination of transforming growth factor (TGF)-β/IL-6 or IL-21, requires expression of the transcription factor retinoic acid receptor–related orphan receptor γt (RORγt). We identify the nuclear receptor peroxisome proliferator–activated receptor γ (PPARγ) as a key negative regulator of human and mouse Th17 differentiation. PPARγ activation in CD4+ T cells selectively suppressed Th17 differentiation, but not differentiation into Th1, Th2, or regulatory T cells. Control of Th17 differentiation by PPARγ involved inhibition of TGF-β/IL-6–induced expression of RORγt in T cells. Pharmacologic activation of PPARγ prevented removal of the silencing mediator for retinoid and thyroid hormone receptors corepressor from the RORγt promoter in T cells, thus interfering with RORγt transcription. Both T cell–specific PPARγ knockout and endogenous ligand activation revealed the physiological role of PPARγ for continuous T cell–intrinsic control of Th17 differentiation and development of autoimmunity. Importantly, human CD4+ T cells from healthy controls and MS patients were strongly susceptible to PPARγ-mediated suppression of Th17 differentiation. In summary, we report a PPARγ-mediated T cell–intrinsic molecular mechanism that selectively controls Th17 differentiation in mice and in humans and that is amenable to pharmacologic modulation. We therefore propose that PPARγ represents a promising molecular target for specific immunointervention in Th17-mediated autoimmune diseases such as MS.
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影响因子：
64.5
作者：
Ivanov, Ivaylo I.;McKenzie, Brent S.;Littman, Dan R.
通讯作者：
Littman, Dan R.
影响因子：
30.5
作者：
Manel, Nicolas;Unutmaz, Derya;Littman, Dan R.
通讯作者：
Littman, Dan R.
影响因子：
64.8
作者：
Pascual, G;Fong, AL;Glass, CK
通讯作者：
Glass, CK
DOI：
10.1073/pnas.2536828100
发表时间：
2003-12-23
影响因子：
11.1
作者：
He, WM;Barak, Y;Evans, RM
通讯作者：
Evans, RM
DOI：
10.1006/scel.1994.1015
发表时间：
1994-01-01
期刊：
Seminars in Cell Biology
影响因子：
--
作者：
Chambon, Pierre
通讯作者：
Chambon, Pierre