Replicative senescence of CD8 T cells: effect on human ageing.
Elderly persons have been exposed to a myriad of pathogens over their lifespan. This life-long immunological history leads, in some cases, to the generation of expanded populations of memory CD8 T cells that have reached the end stage of replicative senescence. In cell culture, CD8 T cells that are subjected to repeated rounds of antigen-driven proliferation eventually show irreversible cell cycle arrest, permanent and complete loss of CD28 gene expression, apoptosis resistance, reduced gene transcription of the major stress protein in response to heat shock, and shortened telomeres compared to their CD28-expressing progenitors. Clinical studies have documented that high proportions of CD8 T cells that lack CD28 are correlated with reduced antibody response to influenza vaccination and are also an immune marker of increased risk of mortality in persons greater than 80 years of age. In addition, CD8 T cells lacking CD28 expression have been documented to have suppressive influences on immune function. Thus, senescent CD8 T cells may affect immune function both directly and indirectly by modulating other immune cell types. The potential role of senescent T cells in bone homeostasis is suggested as a potentially fruitful area for future investigation. The patterns of cytokine changes observed during the progression to senescence in cell culture are consistent with this possibility, and T cells producing these same cytokines have, in fact, been identified within the bone marrow in murine models of osteoporosis. Interestingly, CD8 T cells with markers of replicative senescence are correlated with increased osteoporotic fractures in the elderly. Thus, senescent CD8 T cells are associated with a variety of deleterious health-related outcomes, suggesting that these cells may exert pleiotropic negative effects on both immune and non-immune organ systems during ageing.