Department of Immunology, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo, Japan.
Immunol Cell Biol. 2017 Nov;95(10):906-915. doi: 10.1038/icb.2017.61. Epub 2017 Jul 19.
Respiratory syncytial virus (RSV) is a common virus that causes lower respiratory infections across a wide range of ages. A licensed RSV vaccine is not available because vaccination with formalin-inactivated RSV (FI-RSV) and the subsequent RSV infection cause not only insufficient induction of neutralizing antibodies but also severe allergic airway responses, termed FI-RSV vaccine-enhanced disease (FI-RSV VED). However, the underlying mechanism has not been identified, although a Th2-biased immune response is known to be a hallmark of this disease. Our previous studies have shown that growth arrest-specific 6 (Gas6)/Axl signaling leads to Th2-biased immune responses during fungus-induced allergic airway inflammation. Here, we show that Gas6/Axl signaling also leads to FI-RSV VED and partially identify the mechanism in mice. Inhibiting Gas6/Axl signaling using Gas6-deficient mice, neutralizing antibodies, and a specific inhibitor of Axl attenuated allergic airway hyperresponsiveness, including airway inflammation, goblet cell hyperplasia, and Th2 cytokine production, in addition to increasing interferon-γ levels and the production of RSV-neutralizing IgG2a in FI-RSV VED. Gas6 was produced in lymph nodes during immunization with FI-RSV. Lymph node cells derived from immunized mice produced high levels of Gas6 and Th2 cytokines, but not IFN-γ, after restimulation with RSV. Finally, we found that dendritic cells stimulated with RSV-glycoprotein (G protein) produced Gas6 and that Axl signaling suppressed DC maturation and the induction of IL-12 production by the toll-like receptor 4 agonist RSV-fusion protein. Taken together, these results indicate that RSV-G protein-induced Gas6/Axl signaling causes allergic airway responses during FI-RSV VED.
呼吸道合胞病毒（RSV）是一种常见病毒，可导致广泛年龄段的下呼吸道感染。由于福尔马林灭活 RSV（FI-RSV）疫苗接种和随后的 RSV 感染不仅不能充分诱导中和抗体，而且还会引起严重的过敏气道反应，称为 FI-RSV 疫苗增强疾病（FI-RSV VED），因此尚未开发出 RSV 的许可疫苗。然而，其潜在机制尚未确定，尽管已知 Th2 偏向性免疫反应是该疾病的特征。我们之前的研究表明，生长停滞特异性基因 6（Gas6）/AXL 信号在真菌诱导的过敏气道炎症中导致 Th2 偏向性免疫反应。在这里，我们表明 Gas6/Axl 信号也导致 FI-RSV VED，并在小鼠中部分确定了该机制。使用 Gas6 缺陷型小鼠、中和抗体和 Axl 的特异性抑制剂抑制 Gas6/Axl 信号可减轻过敏气道高反应性，包括气道炎症、杯状细胞增生和 Th2 细胞因子产生，同时增加 IFN-γ 水平和 RSV 中和 IgG2a 的产生。在 FI-RSV 免疫接种期间，Gas6 在淋巴结中产生。用 FI-RSV 免疫的小鼠的淋巴结细胞在重新刺激 RSV 后产生高水平的 Gas6 和 Th2 细胞因子，但不产生 IFN-γ。最后，我们发现用 RSV-糖蛋白（G 蛋白）刺激的树突状细胞产生 Gas6，并且 Axl 信号抑制了树突状细胞成熟和 Toll 样受体 4 激动剂 RSV-融合蛋白诱导的 IL-12 产生。总之，这些结果表明，RSV-G 蛋白诱导的 Gas6/Axl 信号导致 FI-RSV VED 期间的过敏气道反应。
