Functional importance of CD4⁺ and CD8⁺ cells in cytotoxic lymphocytes activity and associated gene expression. Impact on the age‐related decline in lytic activity

Previously we found that the age-related decline in cytotoxic lymphocyte (CTL) activity in a murine allogeneic system is associated with declining expression of the perforin and two serine esterase genes by senescent CTL. To identify the cell subsets responsible for the age-related decrement in the generation of CTL, splenic T cells, subsets, and mixtures of subsets from aging and young BALB/c female mice were analyzed for their allo-responsiveness to C57BL/6 spleen cells. Depletion studies revealed that CD8+ cells expressed both the lytic activity and the CTL-associated genes, although both CD8+ and CD4+ cells were required for generation of optimal lytic and proliferative responses. Mixture experiments demonstrated that the reduced lytic activity generated by CD8+ cells from the spleens of old mice is a consequence of alterations in both CD8+ and CD4+ cells. The results of experiments in which CD4+ cells from young and old mice were mixed revealed that the alteration in CD4+ cells is consistent with a loss of function. These findings show that (a) the expression of the perforin and serine esterase genes in primary CTL is associated with CD8+ T cells in old and young mice, and exhibits an age-related decrement consistent with that for lytic activity, and (b) the senescent decline in CTL activity is a consequence of aging decreasing activity in both the CD4+ and CD8+ subsets.