Notch1 signaling and regulatory T cell function
Notch1 signaling and regulatory T cell function
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DOI：
10.4049/jimmunol.180.5.2796
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发表时间：
2008-03-01
影响因子：
4.4
通讯作者：
Strober, Warren
中科院分区：
文献类型：
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作者：
Asano, Naoki;Watanabe, Tomohiro;Strober, Warren
先前的研究表明，Notch1 和 TGF-β 信号通路是相互增强的。鉴于最近的证据表明调节性 T 细胞 (Treg) 效应器功能是由 TGF-β 信号传导介导的，我们研究了 Notch1 信号传导是否也参与了 Treg 效应器功能。初步研究表明，Notch1 配体，特别是 Jagged1，存在于 Tregs 上，并且事实上，用抗 jagged1 或阻断性抗 Notch1 Ab 阻断 Notch1 信号传导会在体外抑制 Treg 抑制功能。然后我们发现，树突状细胞的 Notch1 激活（Notch1 胞内结构域）产生的信号传导成分与 TGF-β 信号传导 (pSmad3) 产生的信号传导成分发生物理相互作用。此外，这种相互作用具有功能性下游效应，因为 Notch1 胞内结构域的过度表达促进 pSmad3 易位到细胞核，并增强与荧光素酶报告基因连接的 Smad 敏感启动子的 pSmad3 转录活性。最后，我们证明阻断 TGF-β 信号和 Notch 信号不会对 Treg 抑制功能产生附加抑制作用。这些结果与 Notch1 信号传导促进 TGF-β 介导的 Tregs 效应功能的结论一致。
Previous studies have shown that the Notch1 and TGF-beta signaling pathways are mutually re-enforcing. Given recent evidence that regulatory T cell (Treg) effector function is mediated by TGF-beta signaling, we investigated whether Notch1 signaling also participated in Treg effector function. Initial studies showed that Notch1 ligands, particularly Jagged1, are present on Tregs and that, indeed, blockade of Notch1 signaling with an anti-jagged1 or a blocking anti-Notch1 Ab inhibits Treg suppressor function in vitro. We then showed that a signaling component generated by Notch1 activation (Notch1 intracellular domain) of dendritic cells physically interacts with a signaling component generated by TGF-beta signaling (pSmad3). Furthermore, this interaction has functional downstream effects because over-expression of Notch1 intracellular domain facilitates pSmad3 translocation to the nucleus and enhances pSmad3 transcriptional activity of a Smad-sensitive promoter linked to a luciferase reporter. Finally, we showed that blockade of TGF-beta signaling and Notch signaling did not have additive inhibitory effects on Treg suppressor function. These results are consistent with the conclusion that Notch1 signaling facilitates TGF-beta-mediated effector function of Tregs.