Age-related decrement in cytotoxic T lymphocyte (CTL) activity is associated with decreased levels of mRNA encoded by two CTL-associated serine esterase genes and the perforin gene in mice.
The age-related decline in cytotoxic T lymphocyte (CTL) activity has been recognized for many years. Age-related alterations in several immunologic events have been suggested to be partly or completely responsible for this decline. We had previously demonstrated (Bloom et al., Cell. Immunol. 1988. 144: 440) in mice that a deterioration in the lytic mechanism may be at least in part responsible for the decline in CTL activity. We now report that this decline correlates with an age-related decrease in serine esterase activity released into the supernatant medium in the process of generating CTL. Northern analyses were then used to examine the effect of age on expression of genes encoding for perforin and two CTL-associated serine esterases. The products of all three of these genes have all been postulated to play roles in CTL-mediated lysis. We show that the expression of all three of these genes appears to decline with age in the process of generating allogeneic CTL. These alterations in gene expression correlated both with diminished cytolytic and released esterase activities generated by mixed leukocyte culture in spleen cells of old mice compared to young. The age-related decline in gene expression could not be attributed to shifts in T cell subsets, but CD8+ cells generated by allogeneic stimulation of nylon wool-passed spleen cells from old mice expressed significantly less cytolytic activity than those from young. This report is the first demonstration of an age-related decrease in expression of a functionally related group of genes. In addition, these findings are compatible with the suggested roles for perforin and serine esterase release in CTL-mediated target cell lysis.
Bloom
E T
ET
Division of Cytokine Biology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892.
Umehara
H
H
Bleackley
R C
RC
Okumura
K
K
Mostowski
H
H
Babbitt
J T
JT
D000375:Aging / Q000276:immunology*; D000818:Animals; D015152:Blotting, Northern; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D004950:Esterases / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D008213:Lymphocyte Activation / Q000276:immunology; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology / Q000276:immunology*; D014158:Transcription, Genetic
D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger; D054353:Perforin; D004950:Esterases; C022635:serine esterase