Role of CD8 T Cell Replicative Senescence in Human Aging and in HIV-mediated Immunosenescence

Abstract

As humans age, their immune systems undergo a process known as immunosenescence. This global aging of the immune system is associated with increased susceptibility to infectious diseases and cancer, reduced effectiveness of vaccination, increased autoimmune phenomena, and tissue damage due to dysregulated inflammation. One hallmark feature of immunosenescence is the accumulation of late-differentiated memory CD8 T cells with features of replicative senescence, such as inability to proliferate, absence of CD28 expression, shortened telomeres, loss of telomerase activity, and enhanced secretion of inflammatory cytokines. The proportion of senescent CD8 T cells increases progressively with age, and often consists of oligoclonal populations that are specific for cytomegalovirus (CMV) antigens. In addition, there is evidence that senescent memory CD8 T cells acquire suppressive functions and may also contribute to carcinogenesis. Chronic HIV disease, even when controlled through antiretroviral therapy (ART), is associated with accelerated immunosenescence, as evidenced by the higher numbers of senescent memory CD8 T cells and increased inflammatory milieu. Interestingly, even in HIV disease, a high proportion of late-differentiated, putatively senescent, memory CD8 T cells are specific for CMV antigens. As in age-related immunosenescence, these HIV-associated changes result in dysregulated immunity, chronic diseases linked to inflammatory damage, and increased morbidity and mortality. This review explores the evidence for CD8 T cell replicative senescence in vitro and in vivo, in the context of both chronological aging and HIV-mediated immunosenescence. We also highlight an important gap in our understanding of human immunosenescence, since all the studies to date have focused on peripheral blood, which contains a minority of the total body lymphocyte population.