Retinoic acid increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TGF-beta-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression.
Retinoic acid increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TGF-beta-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression.
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DOI：
10.4049/jimmunol.181.4.2277
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发表时间：
2008-08-15
期刊：
影响因子：
--
通讯作者：
Kuchroo VK
中科院分区：
文献类型：
--
作者：
Xiao S;Jin H;Korn T;Liu SM;Oukka M;Lim B;Kuchroo VK
外周免疫区室中Foxp 3+调节性T（Treg）细胞的从头产生和Th 17细胞的分化都需要TGF-β，并且IL-6和IL-21是以Treg产生为代价驱动Th 17细胞发育的开关因子。维生素A的主要代谢产物全反式维甲酸（all-transretinoic acid，RA）不仅促进Treg的产生，而且抑制Th 17细胞的分化。在这里，我们发现RA通过增加Smad 3的表达和磷酸化来增强TGF-β信号传导，这导致即使在IL-6或IL-21存在下Foxp 3表达也增加。RA还抑制IL-6 R α、IRF-4和IL-23 R的表达，从而抑制Th 17的发育。在体外，RA显着促进Treg转化，但在体内实验性自身免疫性脑脊髓炎（EAE）的发展过程中，它不会增加Treg细胞的频率在面对正在进行的炎症。然而，RA通过抑制促炎性T细胞应答，特别是致病性Th 17应答，非常有效地抑制疾病。这些数据不仅确定了RA可以影响Treg和Th 17分化的信号传导机制，而且还强调了在体内自身免疫反应期间，RA主要通过抑制效应Th 17细胞的产生来抑制自身免疫。免责声明：这是一个作者制作的版本的手稿接受发表在免疫学杂志（JI）。美国免疫学家协会(AAI)JI的出版商拥有本手稿的版权。这份手稿尚未由联合执行机构进行编辑或编辑校对;因此可能与联合执行机构（在线和印刷版）公布的最终版本不同。AAI（JI）对作者制作的手稿版本或美国国立卫生研究院或任何其他第三方从中衍生的任何版本中的错误或遗漏不承担责任。记录的最终可引用版本可在www.jimmunol.org上找到。
The de novo generation of Foxp3+ regulatory T (Treg) cells in the peripheral immune compartment and the differentiation of Th17 cells both require TGF-β, and IL-6 and IL-21 are switch factors that drive the development of Th17 cells at the expense of Treg generation. The major vitamin A metabolite all-trans retinoic acid (RA) not only enforces the generation of Treg but also inhibits the differentiation of Th17 cells. Here we show that RA enhances TGF-β signaling by increasing the expression and phosphorylation of Smad3 and this results in increased Foxp3 expression even in the presence of IL-6 or IL-21. RA also inhibits the expression of IL-6Rα, IRF-4 and IL-23R and thus inhibits Th17 development. In vitro, RA significantly promotes Treg conversion but in vivo during the development of experimental autoimmune encephalomyelitis (EAE) it does not increase the frequency of Treg cells in the face of an ongoing inflammation. However, RA suppresses the disease very efficiently by inhibiting proinflammatory T cell responses, especially pathogenic Th17 responses. These data not only identify the signaling mechanisms by which RA can affect both Treg and Th17 differentiation, but also highlight that in vivo during an autoimmune reaction, RA suppresses autoimmunity mainly by inhibiting the generation of effector Th17 cells. Disclaimer: This is an author-produced version of a manuscript accepted for publication in The Journal of Immunology (The JI). The American Association of Immunologists, Inc. (AAI), publisher of The JI, holds the copyright to this manuscript. This manuscript has not yet been copyedited or subjected to editorial proofreading by The JI; hence it may differ from the final version published in The JI (online and in print). AAI (The JI) is not liable for errors or omissions in this author-produced version of the manuscript or in any version derived from it by the United States National Institutes of Health or any other third party. The final, citable version of record can be found at www.jimmunol.org.
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