γδ T cells protect against LPS‐induced lung injury

IL4‐expressing γδ T cells decrease TNF‐α production by alveolar macrophages, reducing accumulation of M1 macrophages that promotes lung injury. γδ T lymphocytes are a unique T cell population with important anti‐inflammatory capabilities. Their role in acute lung injury, however, is poorly understood but may provide significant insight into lung‐protective mechanisms occurring after injury. In a murine model of lung injury, wild‐type C57BL/6 and TCRδ−/− mice were exposed to Escherichia coli LPS, followed by analysis of γδ T cell and macrophage subsets. In the absence of γδ T cells, TCRδ−/− mice developed increased inflammation and alveolar‐capillary leak compared with wild‐type C57BL/6 mice after LPS exposure that correlated with expansion of distinct macrophage populations. Classically activated M1 macrophages were increased in the lung of TCRδ−/− mice at d 1, 4, and 7 after LPS exposure that peaked at d 4 and persisted at d 7 compared with wild‐type animals. In response to LPS, Vγ1 and Vγ7 γδ T cells were expanded in the lung and expressed IL‐4. Coculture experiments showed decreased expression of TNF‐α by resident alveolar macrophages in the presence of γδ T cells that was reversed in the presence of an anti‐IL‐4‐blocking antibody. Treatment of mice with rIL4 resulted in reduced numbers of M1 macrophages, inflammation, and alveolar‐capillary leak. Therefore, one mechanism by which Vγ1 and Vγ7 γδ T cells protect against LPS‐induced lung injury is through IL‐4 expression, which decreases TNF‐α production by resident alveolar macrophages, thus reducing accumulation of M1 macrophages, inflammation, and alveolar‐capillary leak.