Thus, these cells are highly adapted to combat CMV reactivation.
One important cytokine that modulates NK cell function is IL-2 [120]. This is very important as it has been shown that IFNγ produced by NK cells from vaccinated adults challenged with various viruses, including influenza virus are largely dependent on IL-2 secreted by specific T cells in PBMCs [121, 122]. In elderly, stimulation of NK cells with IL-2 resulted in decreased IFNγ production compared to young individuals [123]. This was reinforced by a decreased signaling in NK cells under IL-2 stimulation [124]. Ultimately, the production of IL-2 is also decreased with aging [125]. So, the decreased NK functions are also due to the extrinsic decrease in IL-2 and the intrinsic alteration of IL-2-initiated signaling; however, very few data exist on the changes with age of the CD25 on NK cells [126, 127].
Table 1. Age- and CMV-dependent phenotypic and functional changes in NK cells
Moreover, recently immunometabolism became an area of intense research. This is dependent on the possibility to switch from OXPHOS to aerobic glycolysis, exhibited by activated lymphocytes [128]. NK cells are not exempt from this effect on cell metabolism [120, 129]. The reactive NK cells show a hyperactive Akt-mTOR signaling pathway during steady state. Under stimulation through activating NK cell receptors, the Akt-mTOR pathway induces the increase in calcium influx and lymphocyte function associated antigen 1 integrin activation as a hallmark of reactive NK cells. mTORC1 signaling in activated NK cells is necessary to induce NK cell effector molecules such as IFNγ and GrzB [130, 131]. Concomitantly, this activation is fundamental to the glycolytic reprogramming of the NK cells, assuring effector functions by producing IFNγ and GrzB [129]; however, this is still controversial [132, 133]. During activation, the mitochondrial mass and mitochondrial membrane potential in human NK cells are increasing, which depends on the increase in the expression of the transcriptional cofactor PGC-1α under Il-2 stimulation [134]. It was shown that in NK cells of aged individuals, the impaired IL-2-triggered signaling pathway as well as the no increase in mitochondrial functions and no switch in metabolism is a feature of their senescence, explaining the decreased global effector functions of NK cells in aging [120]. These signaling alterations are due to the inhibition of PGC-1α in NK cells of elderly.
Concomitant to the memory-like NK cells, CMV may also induce the expansion of cytokine induced memory-like NK cells [135, 136]. Under IL-12, IL-18 and IL-15 stimulation, the memory-like NK cells manufacture high quantities of IFNγ and show increased cytotoxicity, but this functionality is very quickly lost [137, 138]. However, if they express IL-2R (CD25), they can be reactivated by very small amount of IL-2 as may be seen in an inflammatory milieu such as aging or during vaccination [38, 103, 104, 139, 140]. Thus, these cells may be an important player (booster) of the organismal defense system when the subjects are vaccinated with the same antigen that the subjects already encountered earlier in some way [14].
There are numerous studies addressing the question of the NK cell response to human CMV during aging [86, 87] (Table 1). As mentioned, under CMV infection around 50% of the NK compartment may be NKG2Cbright, while a proportion of NKG2Cdim NK cells may be also found as in CMV–subjects [44]. However, it seems that this proportion does not increase with aging per se [44, 71, 141]. This is very important as this signifies that the proportion of these cells is already determined during the primary infection independently of the age of the subject and the repetitive CMV reactivation during aging [73, 74]. Moreover, it was found that the memory CD8+ T cells are inversely proportional to their NK cell counterpart [142]. This suggests that a vigorous NK cell response may slow the progression of CMV-driven immunosenescence, and autoimmunity by preventing the accumulation of CMV-specific and late-differentiated T cells can become functionally exhausted in old age [18]. Together, it was shown that accumulation of CMV-driven NKG2C+ NK cells is associated with increased function in the NK cell compartment.
Vaccination in the Elderly
The old paradigm states that the response of elderly to vaccinations is poorer than that of young and middle-aged individuals [1, 143]. Approaches to bypass this problem include revaccinations, higher dosages of the vaccines, and adjuvants [3, 4, 144]. However, currently there are several vaccines recommended (or even designed) for old subjects to prevent vaccine-preventable infectious diseases [144]. The most important are the annual influenza vaccine, the pneumococcal vaccine and the vaccine against varicella zoster [9, 145]. The recommendations are different depending on the country.
As described above for NK cells, there are changes