Altered IL-7Ralpha expression with aging and the potential implications of IL-7 therapy on CD8+ T-cell immune responses.

We investigated the effects of aging on the IL-7-mediated CD8+ T-cell survival pathway and of IL-7 therapy on T-cell immunity. Cells expressing IL-7 receptor (IL-7R) alphahigh and alphalow were identified in a CD45RA+ effector memory (EM(CD45RA+), CD45RA+CCR7-) CD8+ T-cell subset. Elderly subjects (65 years and older) had an increased frequency of EM(CD45RA+) IL-7Ralphalow) CD8+ T cells, leading to decreased STAT5 phosphorylation and survival responses to IL-7 compared with young subjects (40 years and younger). These EM(CD45RA+) IL-7Ralphalow cells were largely antigen experienced (CD27-CD28-), replicatively senescent (CD57+), and perforinhigh CD8+ T cells that had decreased IL-7Ralpha mRNA, independent of guanine and adenine binding protein alpha (GABPalpha) and growth factor independence-1 (GFI1) expression. In measuring T-cell receptor (TCR) repertoires of EM(CD45RA+) CD8+ T cells, the elderly had a limited repertoire in IL-7Ralphahigh and IL-7Ralphalow cells, whereas the young had a diverse repertoire in IL-7Ralphahigh but not in IL-7Ralphalow cells. These findings suggest that aging affects IL-7Ralpha expression by EM(CD45RA+) CD8+ T cells, leading to impaired signaling and survival responses to IL-7, and that IL-7 therapy may improve the survival of EM(CD45RA+) CD8+ T cells with a diverse TCR repertoire in the young but not in the elderly.