LIGHT of pulmonary NKT cells annihilates tissue protective alveolar macrophages in augmenting severe influenza pneumonia

CD1d-restricted natural killer T (NKT) cells are innate-like T lymphocytes with protective or pathogenic roles in the development of influenza pneumonia. Here, we show that lung-infiltrated and activated NKT cells are the major cellular source of LIGHT/TNFSF14, which determines the severity of pulmonary pneumonia by highly deteriorative influenza A virus (IAV) infection. Compared to wild-type mice, LIGHT−/− mice exhibit much lower morbidity and mortality to IAV, due to alleviated lung damage and reduced apoptosis of alveolar macrophages (AMs). LIGHT preferentially promotes cell death of lymphotoxin β receptors positive (LTβR+) AMs but not herpesvirus entry mediator positive (HVEM+) AMs. Therefore, these results suggest that NKT-derived LIGHT augments cell death of the tissue protective AMs in exacerbating lung pathology and susceptibility to fatal influenza infection. Suppression of LIGHT signaling might be a viable option in the treatment of influenza-associated acute respiratory distress syndrome.