Notch ligand Delta-like 4 regulates disease pathogenesis during respiratory viral infections by modulating Th2 cytokines.
Notch ligand Delta-like 4 regulates disease pathogenesis during respiratory viral infections by modulating Th2 cytokines.
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Notch配体三角洲样4通过调节Th2细胞因子调节呼吸道病毒感染期间疾病发病机理。
DOI：
10.1084/jem.20070661
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发表时间：
2007-11-26
影响因子：
15.3
通讯作者：
Lukacs, Nicholas W
中科院分区：
文献类型：
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作者：
Schaller, Matthew A;Neupane, Rupak;Rudd, Brian D;Kunkel, Steven L;Kallal, Lara E;Lincoln, Pamela;Lowe, John B;Man, Yunfang;Lukacs, Nicholas W
最近的数据表明，调节免疫应答的一类重要的指导性信号是Notch配体介导的活化。使用定量聚合酶链反应，我们观察到，只有Delta-like 4（dll 4）在呼吸道合胞病毒（RSV）感染后骨髓来源的树突状细胞上上调，并且它依赖于MyD 88介导的途径。使用对dll 4特异的多克隆抗体，检查RSV诱导的疾病的发展。与对照抗体处理的动物相比，用抗dll 4处理的动物具有显著增加的气道高反应性。当检查淋巴细胞肺浸润时，观察到总CD 4 + T细胞和活化（穿孔素+）CD 8 + T细胞显著增加。分离的肺CD 4 + T细胞表现出Th 2型细胞因子的显著增加和干扰素γ的减少，表明与疾病发病机制的增加相关。平行的体外研究检查了dll 4与白细胞介素-12的整合作用，表明这两种指导性信号一起将免疫应答导向更有效、致病性更低的抗病毒应答。这些数据表明dll 4介导的Notch活化是抗病毒免疫的一种调节剂。
Recent data have indicated that an important instructive class of signals regulating the immune response is Notch ligand–mediated activation. Using quantitative polymerase chain reaction, we observed that only Delta-like 4 (dll4) was up-regulated on bone marrow–derived dendritic cells after respiratory syncytial virus (RSV) infection, and that it was dependent on MyD88-mediated pathways. Using a polyclonal antibody specific for dll4, the development of RSV-induced disease was examined. Animals treated with anti-dll4 had substantially increased airway hyperresponsiveness compared with control antibody-treated animals. When the lymphocytic lung infiltrate was examined, a significant increase in total CD4+ T cells and activated (perforin+) CD8+ T cells was observed. Isolated lung CD4+ T cells demonstrated significant increases in Th2-type cytokines and a decrease in interferon γ, demonstrating an association with increased disease pathogenesis. Parellel in vitro studies examining the integrated role of dll4 with interleukin-12 demonstrated that, together, both of these instructive signals direct the immune response toward a more competent, less pathogenic antiviral response. These data demonstrate that dll4-mediated Notch activation is one regulator of antiviral immunity.