Janssen WJ. Fas ligand-expressing lymphocytes enhance alveolar macrophage apoptosis in the resolution of acute pulmonary inflammation. Am J Physiol Lung Cell Mol Physiol 307: L62-L70, 2014. First published May 16, 2014 doi:10.1152/ajplung.00273.2013.-Apoptosis of alveolar macrophages and their subsequent clearance by neighboring phagocytes are necessary steps in the resolution of acute pulmonary inflammation. We have recently identified that activation of the Fas death receptor on the cell surface of macrophages drives macrophage apoptosis. However, the source of the cognate ligand for Fas (FasL) responsible for induction of alveolar macrophage apoptosis is not defined. Given their known role in the resolution of inflammation and ability to induce macrophage apoptosis ex vivo, we hypothesized that T lymphocytes represented a critical source of FasL. To address this hypothesis, C57BL/6J and lymphocyte-deficient (Rag-1 Ϫ/Ϫ ) mice were exposed to intratracheal lipopolysaccharide to induce pulmonary inflammation. Furthermore, utilizing mice expressing nonfunctional FasL, we adoptively transferred donor lymphocytes into inflamed lymphocyte-deficient mice to characterize the effect of lymphocyte-derived FasL on alveolar macrophage apoptosis in the resolution of inflammation. Herein, evidence is presented that lymphocytes expressing FasL enhance alveolar macrophage apoptosis during the resolution of LPS-induced inflammation. Moreover, lymphocyte induction of alveolar macrophage apoptosis results in contraction of the alveolar macrophage pool, which occurs in a FasLdependent manner. Specifically, FasL-expressing CD8 ϩ T lymphocytes potently induce alveolar macrophage apoptosis and contraction of the alveolar macrophage pool. Together, these studies identify a novel role for CD8 ϩ T lymphocytes in the resolution of acute pulmonary inflammation. macrophage; resolution; alveolus; apoptosis; Fas ligand ACUTE INFLAMMATION IS CHARACTERIZED by recruitment of leukocytes, including neutrophils and mononuclear cells, to sites of injury or infection. For inflammation to resolve and the tissue to revert to its preinjured state, the recruited leukocytes must be cleared from the site. The processes that regulate the death and removal of neutrophils in the early resolution of inflammation are well described (14). However, the mechanisms that underlie the subsequent removal of macrophages in the resolution of inflammation have garnered less attention. We have recently identified that alveolar macrophages (AM⌽s) undergo apoptosis and local phagocytic clearance during the resolution of pulmonary inflammation and that this is required for the return of macrophage numbers to their preinflammatory levels (23).We have further demonstrated that AM⌽ apoptosis occurs via the extrinsic apoptotic pathway and proceeds through activation of the TNF-related death receptor Fas (CD95) on the macrophage cell surface (23). However, the cellular source of the cognate ligand for Fas (FasL) is unknown (12). The primary goal of the current study was to det...