The AP-1 transcription factor Batf controls T(H)17 differentiation.
The AP-1 transcription factor Batf controls T(H)17 differentiation.
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AP-1 转录因子 Batf 控制 T(H)17 分化。
DOI：
10.1038/nature08114
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发表时间：
2009-07-16
期刊：
影响因子：
64.8
通讯作者：
Murphy, Kenneth M.
中科院分区：
文献类型：
--
作者：
Schraml, Barbara U.;Hildner, Kai;Ise, Wataru;Lee, Wan-Ling;Smith, Whitney A. -E.;Solomon, Ben;Sahota, Gurmukh;Sim, Julia;Mukasa, Ryuta;Cemerski, Saso;Hatton, Robin D.;Stormo, Gary D.;Weaver, Casey T.;Russell, John H.;Murphy, Theresa L.;Murphy, Kenneth M.
激活蛋白1(AP-1)转录因子是Jun、Fos、MAF和激活转录因子(ATF)家族蛋白的二聚体，具有碱性区域和亮氨酸拉链结构域。许多AP-1蛋白含有明确的转录激活结构域(TADS)，但BATF和与之密切相关的BATF3(ReFS)只包含一个碱性区域和亮氨酸拉链，被认为是AP-1活性的抑制因子。在这里，我们表明BATF是产生IL-17的辅助性T细胞(TH17)分化所必需的。BATF−/−小鼠具有正常的Th1和Th2分化，但表现出Th17分化缺陷，并且对实验性自身免疫性脑脊髓炎具有抵抗力。Batf−/−T细胞不能诱导Th17分化所需的已知因子，如RoRγt和细胞因子IL-21(ReFS)。加入IL-21或过表达rORγt均不能完全恢复−/−T细胞IL-17的产生。IL-17启动子是BATF应答的，在TH17分化后，BATF结合了IL-17A/F位点以及IL-17、IL-21和IL-22(Ref)启动子上保守的基因间元件。这些结果表明AP-1蛋白BATF在TH17分化过程中起着关键作用。
Activator protein 1 (AP-1) transcription factors are dimers of Jun, Fos, MAF and activating transcription factor (ATF) family proteins characterized by basic region and leucine zipper domains. Many AP-1 proteins contain defined transcriptional activation domains (TADs), but Batf and the closely related Batf3 (refs) contain only a basic region and leucine zipper and have been considered inhibitors of AP-1 activity. Here we show that Batf is required for the differentiation of IL-17-producing T helper (TH17) cells. TH17 cells comprise a CD4+ T cell subset that coordinates inflammatory responses in host defense but is pathogenic in autoimmunity.Batf −/−mice have normal TH1 and TH2 differentiation, but show a defect in TH17 differentiation, and are resistant to experimental autoimmune encephalomyelitis (EAE).Batf −/−T cells fail to induce known factors required for TH17 differentiation, such as RORγt and the cytokine IL-21 (refs). Neither addition of IL-21 nor overexpression of RORγt fully restores IL-17 production in Batf−/− T cells. The IL-17 promoter is Batf-responsive, and upon TH17 differentiation, Batf binds conserved intergenic elements in the IL-17A/F locus and to the IL-17, IL-21 and IL-22 (ref) promoters. These results demonstrate that the AP-1 protein Batf plays a critical role in TH17 differentiation.
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