Resistance to apoptosis in human CD8+ T cells that reach replicative senescence after multiple rounds of antigen-specific proliferation.

We have established an in vitro culture model of cellular aging in which antigen-specific T cells are stimulated repeatedly to divide until they reach the irreversible state of growth arrest known as "replicative senescence." T lymphocytes that reach replicative senescence in culture show complete loss of CD28 expression, shortened telomeres, undetectable telomerase, and reduced ability to produce heat shock proteins. We now document that in response to treatment with apoptotic stimuli, senescent CD8+ T-cell cultures show reduced apoptosis and diminished caspase 3 activity compared with quiescent early passage cultures from the same donor. Our results suggest that the progressive accumulation of T cells showing many of the hallmarks of replicative senescence during aging, chronic infection, and autoimmune disease may, in part, reflect the diminished capacity of such cells to undergo normal programmed cell death.