High-dimensional analysis reveals a distinct population of adaptive-like tissue-resident NK cells in human lung

The concept of adaptive-like “memory” NK cells has been extensively investigated in recent years. In humans, NK cells with adaptive-like features have been identified in peripheral blood and liver of cytomegalovirus (CMV)-seropositive individuals. The human lung is a major target organ for infections and is also a significant reservoir for CMV. However, it remains unknown whether adaptive-like NK cells can be found in this organ. Using RNAseq and flow cytometry analysis, we here identify a novel adaptive-like KIR + NKG2C + NK cell subset with a CD49a + CD56 bright CD16 − tissue-resident (tr)NK cell phenotype in human lung and in peripheral blood. Adaptive-like lung trNK cells were found to be present independently of adaptive-like CD56 dim CD16 + NK cells, to be hyperresponsive towards target cells, and to exhibit signs of metabolic reprogramming. In conclusion, adaptive-like trNK cells constitute a novel subset of human lung NK cells, likely contributing to unique defense mechanisms in context of infection at this site.