Concluding remarks
Ample evidence has accumulated that NK cells proliferate, mature and differentiate in response to various environmental cues. These responses transform the naive NK cell repertoire, which already varies with host genetic background, into a mature repertoire adapted in terms of activating and self-specific KIR expression, Ctype lectin-like receptor expression, CD16 expression, maturation markers, intracellular signalling molecules and transcription factors. Although this constitutes a memory population of immune effector cells, only in the case of MCMV is there definitive evidence of a mechanism for selective expansion of NK cells with specificity for a particular antigen. A limited number of examples in mice and macaques hint at the possibility of antigen specificity involving an NK cell activating receptor repertoire beyond that currently known, but evidence for the nature of a receptor repertoire specially created for NK cell adaptive responses is lacking. Hence, some ambivalence still exists as to the perceived nature of NK cell memory. In the clearest examples, there is monochromatic recognition of select foreign proteins and non-specific cytokines that enhance secondary effector function. Still to be fully explained is the NK cell antigen specificity similar to that bestowed by clonotypic receptors reported in mice and peptide or other modification of NK cell receptor ligands that tilt the balance towards activation of NK cells with particular receptor constellations. In the latter case, memory for any particular pathogen would reflect collective recognition of multiple ligands with signal integration triggering a select set of NK cells to proliferate and differentiate in a manner that lowered the threshold for activation upon secondary exposure to the same set of environmental cues. This possibility requires only subtle extension of what is already accepted about integration of positive and negative signals to control NK cell activation. A more speculative possibility would be collective memory of specific environmental cues distributed among a network of NK cells, rather than attributable to single antigen-specific cells. In this scenario, NK cells would have evolved to provide context-dependent help through intercellular communications in a manner similar to the establishment of memory with neuronal networks. Much remains to be explained regarding the unanticipated behaviour of NK cells revealed over the last two decades. The massive implications for basic and translational science will continue to drive research on NK cell memory that promises more surprises.
