A selective inhibitor of dipeptidyl peptidase I impairs generation of CD8+ T cell cytotoxic effector function.
CTL express high levels of dipeptidyl peptidase I (DPPI), a granule thiol protease able to convert the zymogen precursors of granzymes A and B into active proteases. In the present studies, the effects of specific inhibition of DPPI on generation of CTL effector functions were examined. When T cell DPPI activity was inhibited by >95% throughout 5-day MLC, a significant reduction in the generation of CD8+ T cell BLT esterase activity (<30% of control) and cytolytic activity (<10% of control) was observed. DPPI inhibition during the second to fourth days of 5-day MLC also was associated with reduced proliferation of CD8+ T cells, but had no effect on CD4+ T cell proliferation or IL-2 production by either population. CTL generated in the continuous presence of DPPI inhibition also exhibited impaired lysis of anuclear erythrocyte targets and diminished killing of nucleated targets by perforin-independent pathways. In contrast, inhibition of DPPI during only the last 24 h of 5-day MLC was associated only with reduced generation of BLT esterase activity and reduced lysis of nucleated targets by perforin-dependent pathways. Repeated or delayed inhibition of DPPI in MLC containing granzyme B-deficient responder cells also impaired generation of cytotoxic activity. These results indicate that DPPI or other DPPI-like protease activities not only are required for the activation of granzymes, but also play a role in the expansion and differentiation of full CD8+ T cell cytolytic activity.
Thiele
D L
DL
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235, USA.
McGuire
M J
MJ
Lipsky
P E
PE
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D020789:Cathepsin C; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D003978:Diazomethane / Q000031:analogs & derivatives* / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology*; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors* / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL
D004151:Dipeptides; D004791:Enzyme Inhibitors; C089960:glycylphenylalanine diazomethyl ketone; D003978:Diazomethane; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D020789:Cathepsin C