response with aging in both the innate and the adaptive parts of the immune system. These changes preclude the success of vaccination in the elderly [1]. As stated above, most of the earlier vaccine studies showed, mainly with the influenza vaccine, a decreased protection in old age [146, 147]. This led to the misconception that vaccination in the elderly is not efficient, which in turn discouraged many doctors to propose them. It is of note that even if from the immunological measurements it seemed that the vaccine was not efficient, from a clinical point of view vaccines decreased overall mortality, hospitalization, myocardial infarction, and even institutionalization in the elderly cohort [148].
Thus, several recent studies appeared to show that vaccination in elderly may be as effective as in adult subjects. The SHINGRIXTM vaccine for varicella zoster is the best example, as this was over 80% effective even in those 80+ [144]. It is of note that this vaccine used an adjuvant which could make the difference, showing that if an adequate vaccine is used, an increased protection may be obtained in elderly [3]. The group of Dr. Larbi also showed no changes in influenza vaccine reaction in Singaporean elderly [6, 7].
Thus, vaccination of elderly with adequate vaccines may overcome changes in the immune system with aging. As described above, the NK cells may be important players in vaccine efficacy; thus, targeting them may also improve the vaccine efficacy in old individuals.
NK Cells, Aging, and Vaccination in the Old
Interestingly, the impact of CMV infection in humans on the efficacy of vaccination, e.g. against influenza depends on the age and the immune status of the individuals [38]. The more subjects are in poor health, the more the antibody titer against CMV is higher and less the vaccination is effective [149]. It is assumed that in old subjects, this should be the case, but in contrast in younger individuals this could be beneficial because of the shorter duration of the CMV infection resulting in a CMV-induced enhancement of the antiviral immunity [150]. Together, CMV infection by modulating the whole immune system may lead to survival advantages in younger age and perhaps in not so younger age also. It seems that age is not the most decisive factor, but the duration of the CMV infection, as chronic infection has a reducing effect on vaccination response of NK cells.
It was very recently shown in a murine model [51], that besides the innate CD8+ T cells [151], NK cells were also major producer of IFNγ to activate the adaptive part of the immune system such as CD4+ T cells and ultimately B cells [27, 152]. It was shown that after influenza vaccination, early production of IFNγ production was mediated by NK cells under the high level of IFN type I produced by adjacent cells in the lymph nodes such as macrophages. This high production of IFNγ has been shown to be essential for the Th1 differentiation; however, prior to this the very early secretion of IFNγ stimulates various cytokine production, including IL-12 but mainly IL-6 [153]. IL-6 will modulate and further increase the IL-6+CD11+ DCs which will ultimately regulate the influenza-specific local B cell response via the Th1 response [51]. In this model, the activation of NK cells resulting in various cytokine production and cell-cell interactions was necessary for efficient influenza vaccine protection. However, this seems to be vaccination-dependent as for the vaccinia virus vaccination the main effector seemed to be the inflammasome pathway.
Very few longitudinal studies exist which may distinguish between the effect of aging and CMV infection [73, 74]. It seems that the presence of the late differentiated NK cells is more determined by the CMV infection as their phenotype and number do not significantly change once the infection is installed. Moreover, aging has much less influence on the accumulation of such cells. However, from an evolutionary point of view, the development of these types of cells may be beneficial not only in adults but also in the elderly. Their aggressive elimination might prove detrimental [154, 155].
Perspective
The described changes in NK cell subpopulations and functions, either due to chronological aging or CMV infection or both, may be druggable and influenced to result in better functioning of the immune system and prolonged health span. These interventions may be directed to modulate the epigenetic changes, the surface molecules such as Tim-3 or HLA-E or the signaling pathways as well as the metabolic switch from OXPHOS to aerobic glycolysis. Together, they will result in better NK functioning to decrease age-related diseases and act as efficient senolytics [156]. The modulation of NK functions may be also explored to render the vaccine more efficient.
Conclusion
With aging, both the phenotype and function of NK cells are affected (Fig. 1). The number of existing subpopulations of NKs renders their evaluation difficult. Presently, we mostly uncovered the changes in the major subtypes characterized by the expression of CD56 and the basic activating and inhibitory molecules. The role of chronic, persistent viral infections is also difficult to separate from the aging process per se. A longitudinal study demonstrated that the late-differentiated CD56dim NK cells (CD57+ NKG2C+ FcRγ–) may be driven less by chronological aging, even less by chronic disease severity, but far more by CMV infection [73]. Nevertheless, aging seems also to influence the accumulation of these dysfunctional NK cells. This has a profound functional implication for old subjects, such as increase in infections, malignancies, cardiovascular diseases, concomitant with the decrease in vaccine efficacy. They are also somehow ineffective in the senescent cell elimination. In the meantime, NK cells may be polyfunctional and cross-react with various microorganisms. The discrepancies in the results of studies in this field suggest that we need more longitudinal studies to be able to better asses the changes with aging and distinguish the effects of aging from latent chronic infections. The modulation of the phenotype and functions of these NK cells may be beneficial in increasing the health span of old subjects.
Acknowledgements
This work was supported by grants from Canadian Institutes of Health Research (CIHR) (No. 106634), the Société des médecins de l’Université de Sherbrooke and the Research Center on Aging of the CIUSSS-CHUS, Sherbrooke, by the Polish Ministry of Science and Higher Education statutory grant 02-0058/07/262 to J.M.W., and by Agency for Science Technology and Research (A*STAR JCO 1434m00115).
Disclosure Statement
The authors have no conflict of interest to declare.