Functional Subsets within Clonally Expanded CD8+ Memory T Cells in Elderly Humans

With advancing age, healthy humans frequently demonstrate large clonal expansions of CD8+ T cells in the peripheral blood, which persist for long periods of time and appear to be maintained as a population of memory cells. We studied nine large T cell clones in five elderly individuals. We noted that in most cases the expanded clones were dominated by cells that did not express CD28, a pivotal molecule in T cell activation, and these clones proliferated poorly in culture. However, nearly all of the clonal expansions had CD28+ fractions and some of these cells appeared to lose CD28 gene expression with stimulation in culture. CD28+ cells demonstrated greater proliferation in both bulk and limiting dilution cultures compared to CD28− cells bearing the same TCR, whereas CD28− cells showed increased perforin expression. Together, these data suggest that loss of CD28 expression marks functional differentiation to cytotoxic memory cells within these clonal expansions and likely within CD8+ memory populations in general.