Markers Associated With Immunosenescence
Persistent CMV infection appears to be a factor involved in the process of immunosenescence. Although there is strong evidence that CMV is associated with the immune dysfunction of aging, the mechanisms underlying this association are not known. It is not clear whether CMV infection is a cause of immunosenescence or, inversely, the latter favors an increased susceptibility to CMV infection/reactivation. In studies of experimental models, Nikolich-Zugich's group showed that CMV infection causes marked changes in the CD8+ T cell pool, namely an increase in this pool and a distorted TCR repertoire diversity, due to expansion of the memory effector cell subpopulation concomitant to a reduced naive subpopulation. Moreover, the CD8+ response of mice infected with murine CMV to superinfection with other viruses was reduced. These authors conclude that CMV can accelerate the impairment of immune responses and the changes in the CD8+ pool that occur in mice during immunosenescence.
In latent/persistent infections, such as in CMV, the stimulation is periodic with cycles of viral dormancy and reactivation. Other studies by Nikolich-Zugich's group suggested that the control of latent infections through specific memory, KLRG1+ and CD8+ T cells is preserved in the elderly and that this immuneactivation does not necessarily contribute to the development of immunosenescence, provided that these cells have been generated during adulthood and not in aged mice. Accumulation of these memory–effector 'senescent' cells was not associated with their loss of function. It would be interesting to confirm these persistent viral experimental data in aged persistent human infections. On the other hand, in chronic active infections, such as latent CMV, HCV and HIV, there is continuous immune stimulation and probably a more rapid progression to immunosenescence.[64,65]
In fact, some studies in aged humans showed that latent CMV infection characteristically induces the production of the proinflammatory mediators, most of which are involved in several age-related illnesses, such as cancer, cardiovascular diseases, Type 2 diabetes and rheumatoid arthritis. In addition, a study demonstrated that CMV seropositivity was associated with a senescent phenotype, that is, a reduction in the frequency of naive T cells and the accumulation of CD45RA-re-expressing late-differentiated effector memory cells. However, the senescent phenotype was not observed in individuals predisposed to longevity, possibly because of a better control of the virus.
CMV infection can result in a skewed CD4+ and CD8+ T-lymphocyte repertoire in elderly individuals. Studies have shown that up to 50% of the CD4+ and CD8+ T lymphocytes can be committed to CMV antigens (i.e., pp65, the main structural protein of the virus and the immunodominant antigen).[59,68,69] Therefore, a marker that can be used to describe the cell exhaustion caused by persistent infection is the loss of CD28 and its accumulation during aging, which correlate with many clinical outcomes, including the reduced capacity to control infectious processes.
Another marker is telomere length, as discussed above. Telomere length in CD8+CD28− and CD8+CD28+ T cells was used to determine the replicative history of each subpopulation in healthy individuals and was significantly shorter in the CD8+CD28− T-cell subpopulation. This finding is consistent with the replication history of these cells, presumably in response to repeated antigen exposure, and indicates that they are displaying a replicative senescence status. These findings are in agreement with those of a previous study showing that memory CD4+ T cells presented shorter telomere length than naive CD4+ T cells.[70,71] Indeed, telomere shortening has been used as a predictor of immunological incompetence in elderly individuals.[61,72]
Cytokine secretion patterns may also serve as a marker to identify immunosenescence, as mentioned above for the CD8+CD28− senescent cells. In addition, an ex vivo analysis of CD8+CD28− T lymphocytes showed increased expression of caspase-3 when compared with the CD8+CD28+ T-cell subpopulation, suggesting a higher susceptibility of apoptosis in senescent lymphocytes. However, the survival of terminally differentiated T cells is a controversial issue. A lack of significant differences in the activation of caspase-8 and -3 in CD4+ and CD8+ memory effector T lymphocytes between young and older individuals has been reported, suggesting that these cells have developed apoptosis resistance. The changes in the cytokine secretion pattern and the incapacity of these cells to respond appropriately to stimuli appear to be central events in immunological deficiency in the elderly, as represented by the higher risk of infections, autoimmunity and cancer.[74,75]
Immunotherapy. 2013;5(8):879-893. © 2013 Future Medicine Ltd.