Epigenetic Regulation of Adaptive NK Cell Diversification

Natural killer (NK) cells were previously considered to represent short-lived, innate lymphocytes. However, mouse models have revealed expansion and persistence of differentiated NK cell subsets in response to cytomegalovirus (CMV) infection, paralleling antigen-specific T cell differentiation. Congruently, analyses of humans have uncovered CMV-associated NK cell subsets characterized by epigenetic diversification processes that lead to altered target cell specificities and functional capacities. Here, focusing on responses to viruses, we review similarities and differences between mouse and human adaptive NK cells, identifying molecular analogies that may be key to transcriptional reprogramming and functional alterations. We discuss possible molecular mechanisms underlying epigenetic diversification and hypothesize that processes driving epigenetic diversification may represent a more widespread mechanism for fine-tuning and optimization of cellular immunity.

TrendsNatural killer (NK) cells can form persistent memory in response to infections, most notably cytomegalovirus (CMV).NK cells involved in such long-lasting adaptations to CMV display characteristic yet variable expression of surface receptors and intracellular signaling proteins as a result of cellular selection and differentiation processes.DNA methylation-associated epigenetic imprints lead to differential expression of signaling proteins. While displaying certain hierarchical patterns, these diversification processes appear largely stochastically distributed.Distinct gene regulations underlie functional specializations of adaptive NK cells.Transcriptional analyses of human and mouse adaptive NK cell differentiation reveal common features, but also suggest significant differences in regulation.Generally, pathogen-associated epigenetic diversification processes may underlie discrete optimization for immune cell memory against infection.