Redefining Memory: Building the Case for Adaptive NK Cells

Abstract

Classically, natural killer (NK) cells have been defined by nonspecific innate killing of virus-infected and tumor cells. However, burgeoning evidence suggests that the functional repertoire of NK cells is far more diverse than has been previously appreciated, thus raising the possibility that there may be unexpected functional specialization and even adaptive capabilities among NK cell subpopulations. Some of the first evidence that NK cells respond in an antigen-specific fashion came from experiments revealing that subpopulations of murine NK cells were able to respond to a specific murine cytomegalovirus (MCMV) protein and that in the absence of T and B cells, murine NK cells also mediated adaptive immune responses to a secondary challenge with specific haptens. These data have been followed by demonstrations of NK cell memory of viruses and viral antigens in mice and primates. Herein, we discuss different forms of NK cell antigen specificity and how these responses may be tuned to specific viral pathogens, and we provide assessment of the current literature that may explain molecular mechanisms of the novel phenomenon of NK cell memory.

Keywords: immune memory; innate immunity; natural killer cells.

FIG 1

Examples of antigen-specific, cytokine-induced, and memory-like NK cells in mice and humans/nonhuman primates (NHP). Venn diagrams represent examples of evidence for adaptive NK cells and whether these have been demonstrated as being truly antigen specific, cytokine induced, and memory-like or a combination of these. Microbial pathogens or other agents for which memory NK cells have been demonstrated are color coded. Ellipses indicated those agents that have been demonstrated in mice (dashed line) or humans/NHP (solid line). AML, acute myeloid leukemia; VLP, virus-like particles.