CD25-expressing CD8+ T cells are potent memory cells in old age

We have recently described an IL-2/IL-4-producing CD8(+)CD25(+) nonregulatory memory T cell population that occurs in a subgroup of healthy elderly persons who characteristically still have a good humoral response after vaccination. The present study addresses this specific T cell subset and investigates its origin, clonal composition, Ag specificity, and replicative history. We demonstrate that CD8(+)CD25(+) memory T cells frequently exhibit a CD4(+)CD8(+) double-positive phenotype. The expression of the CD8 alpha beta molecule and the occurrence of signal-joint TCR rearrangement excision circles suggest a thymic origin of these cells. They also have longer telomeres than their CD8(+)CD25(-) memory counterparts, thus indicating a shorter replicative history. CD8(+)CD25(+) memory T cells display a polyclonal TCR repertoire and respond to IL-2 as well as to a panel of different Ags, whereas the CD8(+)CD25(-) memory T cell population has a more restricted TCR diversity, responds to fewer Ags, and does not proliferate in response to stimulation with IL-2. Molecular tracking of specific clones with clonotypic primers reveals that the same clones occur in CD8(+)CD25(+) and CD8(+)CD25(-) memory T cell populations, demonstrating a lineage relationship between CD25(+) and CD25(-) memory CD8(+) T cells. Our results suggest that CD25-expressing memory T cells represent an early stage in the differentiation of CD8(+) cells. Accumulation of these cells in elderly persons appears to be a prerequisite of intact immune responsiveness in the absence of naive T cells in old age.