Different contribution of EBV and CMV infections in very long-term carriers to age-related alterations of CD8+ T cells.

Aging is accompanied by a complex dynamics of CD8+ T cell subsets whose origin is unclear. To evaluate the impact of Epstein-Barr virus (EBV) and cytomegalovirus (CMV) chronic infections on CD8+ T cells in far advanced age, we studied CD8+ T cells frequencies and phenotype in nonagenarians and centenarians by HLA-A*0201- and HLA-B*0702-tetramers incorporating epitopes specific of both viruses along with viral replication. The results demonstrate that EBV and CMV infections induce quantitatively and qualitatively different CD8+ T-cell responses in advanced aging. The frequency and absolute number of CD8+ T cells specific for one lytic and two latent EBV-epitopes, were relatively low and mostly included within CD8+ CD28+ cells. By contrast, CMV infection was characterized by highly variable numbers of CD8+ T cells specific for two differently restricted CMV-epitopes that, in some subjects, were strikingly expanded. Moreover, the great majority of anti-CMV CD8+ T cells did not bear CD28 antigen. Notwithstanding the expansion of CMV-specific CD8+ lymphocytes, CMV-DNA detection in blood samples was invariably negative. Altogether, we suggest that CMV, but not EBV, can sustain chronic activation of the HLA-class I restricted effector arm in elderly that might have detrimental effects on age-associated diseases.

Marked increase with age of type 1 cytokines within memory and effector/cytotoxic CD8+ T cells in humans: a contribution to understand the relationship between inflammation and immunosenescence.

The ageing process is characterized by a progressive exhaustion of the naïve T cell reservoir that is accompanied by a compensatory expansion of effector/cytotoxic CD8+CD28- T cells. However, the origin and function of this subpopulation is not completely clarified. In this study, we examined the intracellular cytokine profile in purified CD8+ T cells obtained from 29 healthy subjects of different ages. Type 1 (IFN-gamma IL-2 and TNF-alpha) and type 2 (IL-4, IL-6 and IL-10) cytokines were determined in three CD8+ T subsets, i.e. CD95-CD28+ (naïve), CD95+CD28- (effector/cytotoxic), and CD95+CD28+ (memory). As a general trend, we observed, in aged subjects, an increase of type 1 and type 2 intracellular cytokines within the three CD8+ subsets. In particular, we showed that type 1 cytokine-positive cells significantly increased, with age, among all the CD8+ subsets, while a marked increase of type 2 producing cells was observed only in memory CD8+ T cells. These profound changes are compatible with inflame-aging, an hypothesis which suggest that immunosenescence is mainly driven by a chronic antigenic load which not only induces an enormous expansion of CD28- T cells, but also increases their functional activity, exemplified by an high frequency of cells positive for pro-inflammatory cytokines.