biostudies-literatureJameson GHealth Research Board (HRB)Health Research Boarde2412489121https://www.ebi.ac.uk/biostudies/studies/S-EPMC11494342biostudies-literatureUnknown121(42)Tissue-resident natural killer (trNK) cells are present in the human lung, yet their metabolic function is unknown. NK cell effector and metabolic function are intrinsically linked therefore targeting metabolism presents therapeutic potential in supporting NK cell effector function. This study identifies trNK cells in human bronchoalveolar lavage fluid (BALF) and reveals their distinct metabolic function. To assess the differential phenotype and metabolism of NK cells in the lung, human BALF, and peripheral blood were evaluated by flow cytometry and SCENITH^TM. Published RNA-sequencing datasets of human lung and blood NK cells were repurposed to determine their differential gene expression. We identified CD49a⁺CD69⁺CD103^+/-CD56^brightCD1Proceedings of the National Academy of Sciences of the United States of AmericaHuman tissue-resident NK cells in the lung have a higher glycolytic capacity than non-tissue-resident NK cells in the lung and blood.PMC11494342HRB-ILP-POR-2022-033HRB-EIA-2019-010O'Gallchobhair OMurphy DMJameson GWoods RWalsh AO'Connell FNadarajan PGleeson LEConnolly SADuffin EBasdeo SABatten IKeane JfalseHuman tissue-resident NK cells in the lung have a higher glycolytic capacity than non-tissue-resident NK cells in the lung and blood.Tissue-resident natural killer (trNK) cells are present in the human lung, yet their metabolic function is unknown. NK cell effector and metabolic function are intrinsically linked therefore targeting metabolism presents therapeutic potential in supporting NK cell effector function. This study identifies trNK cells in human bronchoalveolar lavage fluid (BALF) and reveals their distinct metabolic function. To assess the differential phenotype and metabolism of NK cells in the lung, human BALF, and peripheral blood were evaluated by flow cytometry and SCENITH^TM. Published RNA-sequencing datasets of human lung and blood NK cells were repurposed to determine their differential gene expression. We identified CD49a⁺CD69⁺CD103^+/-CD56^brightCD12024-01-01T00:00:00Z2024 Oct2025-04-04T14:37:27.069Z2025-04-04T14:37:27.069ZS-EPMC114943423937809110.1073/pnas.2412489121