A SELECTIVE INHIBITOR OF DIPEPTIDYL PEPTIDASE-I IMPAIRS GENERATION OFCD8(-CELL CYTOTOXIC EFFECTOR FUNCTION() T)

CTL express high levels of dipeptidyl peptidase I (DPPI), a granule th iol protease able to convert the zymogen precursors of granzymes A and B into active proteases, In the present studies, the effects of speci fic inhibition of DPPI on generation of CTL effector functions were ex amined. When T cell DPPI activity was inhibited by >95% throughout 5-d ay MLC, a significant reduction in the generation of CD8(+) T cell BLT esterase activity (<30% of control) and cytolytic activity (<10% of c ontrol) 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 pro duction by either population. CTL generated in the continuous presence of DPPI inhibition also exhibited impaired lysis of anuclear erythroc yte targets and diminished killing of nucleated targets by perforin-in dependent pathways. In contrast, inhibition of DPPI during only the la st 24 h of 5-day MLC was associated only with reduced generation of BL T esterase activity and reduced lysis of nucleated targets by perforin -dependent pathways. Repeated or delayed inhibition of DPPI in MLC con taining 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 g ranzymes, but also play a role in the expansion and differentiation of full CD8(+) T cell cytolytic activity.