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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Notch regulates IL-10 production by T helper 1 cells
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Notch regulates IL-10 production by T helper 1 cells

机译：Notch调节T辅助细胞1产生IL-10

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摘要

T helper 1 (Th1) cells mediate powerful cellular immune responses. However, if unbalanced, Th1 immunity eventually may cause pathology. Recently, it has been shown that IL-10, an antiinflam-matory cytokine strongly antagonizing Th1-mediated effects, can be produced by Th1 cells and is indeed essential for self-regulation of Th1 immunity. Here, we show that Notch induces IL-10 production in newly developing and already established Th1 cells via a signal transducer and activator of transcription 4 (STAT4)-depen-dent process. Notch signaling in the presence of the cytokines IL-12 or IL-27 induces Th1 cells to produce large amounts of IL-10 without diminishing IFN-γ production. Notch-modified Th1 cells completely lose their inflammatory capacity and instead are able to actively suppress a Th1 cell-induced delayed-type hypersensitivity (DTH) reaction in an IL-10-dependent fashion. IL-10 production can be elicited by active forms of all four mammalian Notch receptors but was found to be specific for the Delta-like family of Notch ligands. Dendritic cells (DC) selectively acquire Delta-like 4 expression upon stimulation with various Toll-like receptor (TLR) ligands and con-comitantly induce IL-10 production by Th1 cells in vitro and in vivo. This effect can be selectively reversed by pharmacological inhibitors of Notch signaling (γ-secretase inhibitor). Our data suggest that Notch regulates IL-10 production in Th1 cells by a STAT4-dependent process that converts proinflammatory Th1 cells into T cells with regulatory activity. This pathway may provide unique opportunities for therapeutic intervention in Th1-driven immune diseases and for Th1-associated vaccination strategies.
机译：T辅助1（Th1）细胞介导强大的细胞免疫反应。但是，如果不平衡，Th1免疫力最终可能会导致病理。最近，已经显示出IL-1，一种强烈拮抗Th1介导的作用的抗炎细胞因子IL-10，可以由Th1细胞产生，并且对于Th1免疫力的自我调节确实是必不可少的。在这里，我们显示Notch通过信号转导子和转录4（STAT4）依赖过程的活化剂在新开发和已经建立的Th1细胞中诱导IL-10的产生。在存在细胞因子IL-12或IL-27的情况下，Notch信号传导可诱导Th1细胞产生大量IL-10，而不会减少IFN-γ的产生。 Notch修饰的Th1细胞完全丧失了炎症能力，而是能够以IL-10依赖的方式主动抑制Th1细胞诱导的迟发型超敏反应（DTH）。可以通过所有四个哺乳动物Notch受体的活性形式引发IL-10的产生，但是发现它对Notch配体的Delta样家族具有特异性。树突状细胞（DC）在用各种Toll样受体（TLR）配体刺激后选择性获得Delta样4表达，并在体外和体内伴随诱导Th1细胞产生IL-10。可以通过Notch信号的药理抑制剂（γ-分泌酶抑制剂）选择性地逆转这种作用。我们的数据表明，Notch通过STAT4依赖性过程调节Th1细胞中IL-10的产生，该过程将促炎性Th1细胞转化为具有调节活性的T细胞。该途径可能为Th1驱动的免疫疾病的治疗干预以及Th1相关的疫苗接种策略提供独特的机会。

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