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.
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Division of Cytokine Biology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892.
D000375:Aging / Q000276:immunology*; D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D015704:CD4 Antigens / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016827:CD8 Antigens; D003602:Cytotoxicity, Immunologic; D005260:Female; D015870:Gene Expression; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000032:analysis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000945:Antigens, Differentiation, T-Lymphocyte; D015704:CD4 Antigens; D016827:CD8 Antigens; D012333:RNA, Messenger