GSE158485
A discrete subset of epigenetically primed human NK cells mediates antigen-specific immune responses
Adaptive features of natural killer (NK) cells have been reported in various species with different underlying mechanisms. It is unclear, however, which NK cell populations are capable of mounting antigen-specific recall responses, and how such functions are regulated at the molecular level. Here we identify and characterize a discrete population of CD49a+CD16- NK cells in the human liver that display increased epigenetic potential to elicit memory responses and has the functional properties to exert antigen-specific immunity on the skin as an effector site. Integrated chromatin-based epigenetic and transcriptomic profiling revealed unique characteristics of hepatic CD49a+CD16- NK cells when compared to conventional CD49a-CD16+ NK cells thereby defining active genomic regions and molecules underpinning distinct NK cell reactivity. In contrast to conventional NK cells, our results suggest adaptive CD49a+CD16- NK cells to be able to bypass the KIR receptor-ligand system upon antigen-specific stimulation. Furthermore, these cells were highly migratory towards chemokine gradients expressed in epicutaneous patch test lesions as an effector site of adaptive immune responses of the skin. These results define pathways operative in human antigen-specific memory NK cells and provide a roadmap for harnessing this NK cell subset for specific therapeutic or prophylactic vaccine strategies. Overall design: Bulk RNA sequencing and ATAC-seq sequencing of human liver-derived CD49a+CD16- NK cells and CD49a-CD16+ NK cells upon stimulation with IL-2 (100Ui/ml) and IL-15 (10ng/ml) for 4 hours. RNA sequencing data of CD45+ cells isolated from human liver. This series includes three liver samples enriched for CD45+ cells included, all from different donors. Human liver tissue was flushed with PBS, cut into small pieces with a sterile scalpel, passed through 70-um mesh filters and rinsed with 10% FBS in PBS. Leukocytes of the liver were isolated by density gradient centrifugation using Ficoll gradients. For flow cytometry analysis or cell sorting, cells were stained with fluorescence antibodies.