to human CMV infection [42], a mechanism somewhat similar to the increase in proportions of CD8 T cells specific for CMV epitopes [43, 44]; however, the temporal and spatial features of its accumulation are still not completely resolved.
NK Cell Functions
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].
Collaboration/Interaction with Other Immune Cells
One very interesting property of NK cells is their ability to modulate the functions of other innate and adaptive immune cells. Especially the NK cells interact with the DCs through crosstalk and cytokines [55]. Furthermore, it is well known from in vitro studies and colocalization experiments that NK cells can interact bidirectionally with DCs in areas of inflammation causing DC maturation, a consequent enhancement of NK cell function through positive feedback and exerting an influence on the polarization of primary T cell-responses toward a TH1 response [56–60]. In fact, mature DCs can activate NK cell cytotoxicity (NKCC) and IFNγ production, whereas activated NK cells are capable of enhancing DC maturation and IL-12 production. The previously described interactions are cell contact and TNFα-dependent [56, 61–63]. Furthermore, mature DCs recruit NK cells to the lymph nodes, by producing chemokines including the CXCR3 ligand CXCL9/MIG and substantial amounts of CXCL10/IP-10 and CXCL11/I-TAC where NK cells serve as an early source of the IFNγ necessary for Th1 polarization, possibly by direct interaction with naïve T cells [27]. Thus, this interaction would result in the activation of both cell types. Moreover, NK cells also influence B lymphocyte affinity maturation through the restriction of follicular helper T cells [64]. This is absolutely indispensable for the generation of broadly neutralizing antibodies. In this way, NK cells are largely participating in the efficacy of vaccination [14]. NK cells may also, via the production of IFNγ, participate in the activation of macrophages and T cells.
NK Cells and Aging
As mentioned above, NK cells are powerful protectors from virus-infected, tumor, and senescent cells [25, 65–68].
Proportions and numbers of NK cell subpopulations are affected by aging [18, 69–74] (Fig. 1). For example, the overall percentage of NK cells among peripheral blood lymphocytes is increased in healthy aging and centenarians