The Driving Force

We have recently proposed that latent infection with herpes viruses may constitute a major antigenic stimulus leading to the accumulation of senescent CD8+ T cells in vivo (Pawelec et al., 2004). Elderly persons have large numbers of dysfunctional CD8+ T cells bearing antigen receptors for a single dominant cytomegalovirus (CMV) epitope (Ouyang et al., 2003b). Even in younger persons who are infected with HIV and whose immune systems are thought to age prematurely, there are substantial numbers of CD8+CD28~ T cells that are specific for CMV as well as for Epstein-Barr virus (EBV). These sorts of data suggest that the cost of maintaining control over these latent infections is the progressive generation of senescent CD8+ T cells (Pawelec et al., 2004). The apop-tosis resistance of these cells leads to a situation where they occupy progressively more and more of the memory T cell pool in the elderly, restricting the repertoire of the remaining T cells.

Latent viruses associated with certain forms of cancer can also drive CD8+ T cells to senescence, as illustrated by the accumulation of CD8+CD28~ T cells with reactivity to the human papilloma virus E7 antigen in cervical cancer patients (Pilch et al., 2002). Other viruses associated with chronic infection, such as Hepatitis C, also seem to elicit expanded populations of CD8+ T cells that lack CD28 expression (Kurokohchi et al., 2003). The common thread in all of these situations is chronic antigenic stimulation, which seems to result in massive cell division of antigen-reactive CD8+ T cells, ultimately causing them to reach what might be considered the endstage of their differentiation pathway, namely replicative senescence. Clearly, most memory T cells encounter their nominal antigen only once or twice over an individual's lifespan, and it is only those CD8+ T cells with reactivity to antigens that are never cleared from the body that have the potential to continue dividing extensively, eventually reaching senescence.

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