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 αβ 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.