Human 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. Published RNA-sequencing datasets of human lung and blood NK cells were repurposed to determine their differential gene expression. We identified CD49aCD69CD103CD56CD16 trNK cells in human BALF samples and metabolic profiling revealed that lung CD56CD16 NK cells' glycolytic capacity and dependence on glucose is significantly higher than matched peripheral blood counterparts. This high glycolytic capacity and glucose dependence was attributed to the trNK cell subset which supports the existing evidence that they have an enhanced ability to respond in the lung.