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NK cells are functionally very versatile. However, their main function is cytotoxicity against the cells of the organisms presenting MHC abnormalities, meaning that healthy cells escape the NK cell-mediated cytotoxicity, while virus-infected and transformed cells are their main targets. MHC-I molecules on the normal cells inhibit NK cell activation via inhibitory receptors such as killer immunoglobulin-like receptors (KIRs), leukocyte Ig-like receptor (LIR-1) and, as mentioned earlier, the C-type lectin receptors CD94/NKG2A [18, 45]. In contrast, infected or malignant cells which downregulate MHC-I molecules, express ligands such as MICA, MICB, CD48, ULBP-1 for activating receptors on NK cells, such as NKG2D [46, 47]. This latter interaction would elicit the secretion of “killing” molecules such as pore-forming perforin and granzyme B (GrzB) inducing the apoptosis of the target cells [48], as well as various cytokines and chemokines. These mediators are able to modulate other cells of the immune system. The other pathway of NK-dependent cell killing involves the members of the TNF superfamily of death receptors and their ligands [49].

Very recent studies suggest that NK cells show features typical for the cells belonging to the adaptive branch of the immune system, making them adaptive-like [15]. This was first demonstrated in murine models, whereby the use of the delayed-type hypersensitivity (DTH) challenge has shown that NK cells exhibit all three hallmarks of adaptive immunity, namely: vaccination dependence, antigen specificity, and long-lived immunological memory [29]. It was also demonstrated that this NK response is B and T cell independent [50]. Recently, in a humanized mice model, it was demonstrated that human NK cells with tissue-resident phenotype mediate adaptive immunity similarly as was demonstrated for murine NK cells [29, 30]. Furthermore, human NK cells from varicella-zoster virus (VZV)-experienced humans (via intradermal injection of VZV skin test antigen) elicited a DTH response indicating that VZV-primed NK cells were recalled into the skin and suggesting the existence of their long-term memory [15]. These cells had expressed a high level of cytotoxicity marker CD107a [14].

What this means for a better vaccine efficacy is presently not fully understood. However, the fact that NK cells may present a certain type of long-term immune memory would be an interesting means to improve vaccine efficacy [14–16]. In recent studies, it was discovered that NK cells may mediate robust vaccine-dependent recall response by featuring antigen specificity and long-lasting memory [14]. These NK cells responding to the boost are phenotypically more mature and cytotoxic. The NK cell phenotype after vaccination boost expressed different surface markers compared to those of the prime vaccination-related NK markers such as CD69, CD66, CCR5, CD11a, CD11c, CD16, GrzB, perforin, and CD107a [14]. These markers are again associated with NK maturation and better cytotoxic performance after a boost or cognate infections [52, 53]. It was also demonstrated that some of these markers such as CD16, CCR5, and CD11a are also shared with monocytes, neutrophils, and DCs subjected to boost, which suggests that these NK cells may cross react in a non-Ag-specific manner [54]. However, distinct interactions between NK cells and other innate immune cells suggest an Ag-specific (adaptive-like) response [14].