Department of Microbiology and Immunology, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642;
J Immunol. 2013 Nov 1;191(9):4720-30. doi: 10.4049/jimmunol.1301679. Epub 2013 Sep 27.
Pneumocystis is an atypical fungal pathogen that causes severe, often fatal pneumonia in immunocompromised patients. Healthy humans and animals also encounter this pathogen, but they generate a protective CD4(+) T cell-dependent immune response that clears the pathogen with little evidence of disease. Pneumocystis organisms attach tightly to respiratory epithelial cells, and in vitro studies have demonstrated that this interaction triggers NF-κB-dependent epithelial cell responses. However, the contribution of respiratory epithelial cells to the normal host response to Pneumocystis remains unknown. IκB kinase 2 (IKK2) is the upstream kinase that is critical for inducible NF-κB activation. To determine whether IKK2-dependent lung epithelial cell (LEC) responses contribute to the anti-Pneumocystis immune response in vivo, transgenic mice with LEC-specific deletion of IKK2 (IKK2(ΔLEC)) were generated. Compared to wild-type mice, IKK2(ΔLEC) mice exhibited a delayed onset of Th17 and B cell responses in the lung and delayed fungal clearance. Importantly, delayed Pneumocystis clearance in IKK2(ΔLEC) mice was associated with an exacerbated immune response, impaired pulmonary function, and altered lung histology. These data demonstrate that IKK2-dependent LEC responses are important regulators of pulmonary adaptive immune responses and are required for optimal host defense against Pneumocystis infection. LECs likely set the threshold for initiation of the pulmonary immune response and serve to prevent exacerbated lung inflammation by promoting the rapid control of respiratory fungal infection.
卡氏肺孢子虫是一种非典型的真菌病原体，可导致免疫功能低下的患者发生严重的、常致命性的肺炎。健康的人类和动物也会接触到这种病原体，但他们会产生一种保护性的 CD4(+) T 细胞依赖性免疫反应，清除病原体，几乎没有疾病的证据。卡氏肺孢子虫附着在呼吸道上皮细胞上，体外研究表明，这种相互作用触发了 NF-κB 依赖性的上皮细胞反应。然而，呼吸道上皮细胞对正常宿主对卡氏肺孢子虫的反应的贡献仍不清楚。IKK2 是诱导型 NF-κB 激活的关键上游激酶。为了确定 IKK2 依赖性肺上皮细胞（LEC）反应是否有助于体内抗卡氏肺孢子虫免疫反应，生成了 LEC 特异性缺失 IKK2（IKK2(ΔLEC)）的转基因小鼠。与野生型小鼠相比，IKK2(ΔLEC)小鼠肺部 Th17 和 B 细胞反应的起始时间延迟，真菌清除延迟。重要的是，IKK2(ΔLEC)小鼠中卡氏肺孢子虫清除的延迟与免疫反应的加剧、肺功能受损和肺组织学改变有关。这些数据表明，IKK2 依赖性 LEC 反应是肺部适应性免疫反应的重要调节剂，是宿主抵抗卡氏肺孢子虫感染的最佳防御所必需的。LEC 可能为肺部免疫反应的启动设定了阈值，并通过促进呼吸道真菌感染的快速控制，有助于防止肺部炎症的加剧。
