Research ArticleNK CELLS

A discrete subset of epigenetically primed human NK cells mediates antigen-specific immune responses

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Science Immunology  16 Oct 2020:
Vol. 5, Issue 52, eaba6232
DOI: 10.1126/sciimmunol.aba6232

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Liver NK cells with antigen specificity

Natural killer (NK) cells are heterogeneous innate effector cells, with some NK subsets displaying features of adaptive immunity including memory and antigen specificity. Because liver NK cells are enriched for adaptive NK cells, Stary et al. used RNA sequencing and flow cytometry of human liver NK cells to search for correlations between NK cell phenotypes and their capacity to carry out adaptive effector functions. A CD49a+ CD16 subset of liver NK cells distinct from conventional NK cells expressed a cytotoxicity-associated gene program and exhibited antigen-specific killing of autologous target cells pulsed with viral antigens or metal allergens. Identification of this human hepatic NK subset is an advance in the ongoing quest to understand the molecular basis for antigen-specific recognition by adaptive NK cells.

Abstract

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 displays increased epigenetic potential to elicit memory responses and has the functional properties to exert antigen-specific immunity in the skin as an effector site. Integrated chromatin-based epigenetic and transcriptomic profiling revealed unique characteristics of hepatic CD49a+CD16 NK cells when compared with conventional CD49aCD16+ NK cells, thereby defining active genomic regions and molecules underpinning distinct NK cell reactivity. In contrast to conventional NK cells, our results suggest that adaptive CD49a+CD16 NK cells are able to bypass the KIR receptor-ligand system upon antigen-specific stimulation. Furthermore, these cells were highly migratory toward chemokine gradients expressed in epicutaneous patch test lesions as an effector site of adaptive immune responses in the skin. These results define pathways operative in human antigen-specific adaptive NK cells and provide a roadmap for harnessing this NK cell subset for specific therapeutic or prophylactic vaccine strategies.

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