Memory-like responses of natural killer cells

Abstract

Natural killer (NK) cells are lymphocytes with the capacity to produce cytokines and kill target cells upon activation. NK cells have long been categorized as members of the innate immune system and as such have been thought to follow the 'rules' of innate immunity, including the principle that they have no immunologic memory, a property thought to be strictly limited to adaptive immunity. However, recent studies have suggested that NK cells have the capacity to alter their behavior based on prior activation. This property is analogous to adaptive immune memory; however, some NK cell memory-like functions are not strictly antigen dependent and can be demonstrated following cytokine stimulation. Here, we discuss the recent evidence that NK cells can exhibit properties of immunologic memory, focusing on the ability of cytokines to non-specifically induce memory-like NK cells with enhanced responses to restimulation.

Fig. 1. Enhanced IFN-γ production by memory-like NK cells is maintained for at least 4 weeks

Cytokine-activated (A) Ly5.1⁺ CFSE-labeled NK cells and control-treated (B) Ly5.2⁺ CFSE-labeled NK cells were adoptively co-transferred into a naive Ly5.2 host. Four weeks after adoptive transfer, NK cell were re-stimulated in vitro for four hours with IL-12 and IL-15. Three populations of NK cells were identified based on CFSE and Ly5.1 expression (left panel, gated on NK cells): (A) preactivated NK cells were significantly more likely to produce IFN-γ when compared to (B) control-transferred or (C) host NK cells (representative flow plots shown).

Fig. 2. Model of cytokine-induced NK cell memory-like responses

NK and dendritic cell (DC) cross-talk involves cytokine stimulation as well as cell-contact signals. Following activation and production of IFN-γ, some NK cells might differentiate into memory-like cells, a process that takes less than one week. These memory-like NK cells do not constitutively produce IFN-γ and are maintained in a resting state. However, weeks later, when these NK cells are activated again via NK-DC cross-talk, this pool of memory-like NK cells could provide enhanced IFN-γ and therefore potentially improved protection against pathogens.