Notch signaling regulates mouse and human Th17 differentiation.
Notch signaling regulates mouse and human Th17 differentiation.
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DOI：
10.4049/jimmunol.1003658
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发表时间：
2011-07-15
期刊：
影响因子：
--
通讯作者：
Osborne BA
中科院分区：
文献类型：
--
作者：
Keerthivasan S;Suleiman R;Lawlor R;Roderick J;Bates T;Minter L;Anguita J;Juncadella I;Nickoloff BJ;Le Poole IC;Miele L;Osborne BA
已知T辅助17 （Th17）细胞在对几种重要的细胞外病原体的适应性免疫反应中起关键作用。此外，Th17细胞还参与多种自身免疫性疾病和炎症性疾病以及癌症的发病机制。因此，了解调控Th17分化的机制至关重要。Notch信号在T细胞发育和分化的几个阶段都很重要。在这里，我们报道了Notch1在小鼠和人类体外极化Th17细胞中都被激活，并且Notch信号的阻断显著下调Th17相关细胞因子的产生，这表明在这两个物种中Th17分化过程中都需要Notch。通过启动子报告子分析、敲低研究以及染色质免疫沉淀，我们也提供了证据，证明IL-17和RORγt是Th17细胞中Notch信号的直接转录靶点。最后，在实验性自身免疫性脑脊髓炎（多发性硬化症小鼠模型）中，体内抑制Notch信号可减少IL-17的产生和Th17介导的疾病进展。因此，本研究强调了Notch信号在Th17分化中的重要性，并表明针对Notch的选择性靶向治疗可能是治疗自身免疫性疾病（包括多发性硬化症）的重要工具。
T helper17 (Th17) cells are known to play a critical role in adaptive immune responses to several important extracellular pathogens. Additionally, Th17 cells are implicated in the pathogenesis of several autoimmune and inflammatory disorders as well as in cancer. Therefore, it is essential to understand the mechanisms that regulate Th17 differentiation. Notch signaling is known to be important at several stages of T cell development and differentiation. Here we report that Notch1 is activated in both mouse and human in-vitro polarized Th17 cells and blockade of Notch signaling significantly down-regulates the production of Th17 associated cytokines suggesting an intrinsic requirement for Notch during Th17 differentiation in both species. We also present evidence, using promoter reporter assays, knockdown studies as well as chromatin immunoprecipitation, that IL-17 and RORγt are direct transcriptional targets of Notch signaling in Th17 cells. Finally, in-vivo inhibition of Notch signaling reduced IL-17 production and Th17 mediated disease progression in experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Thus, this study highlights the importance of Notch signaling, in Th17 differentiation and indicates that selective targeted therapy against Notch may be an important tool to treat autoimmune disorders, including multiple sclerosis.
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