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 beta receptors positive (LTbR+) 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. (C) 2021 Science China Press. Published by Elsevier B.V. and Science China Press.