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Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
Since the CTL secreted granule protease granzyme B can activate
multiple target caspases, it has been proposed that this pathway is
responsible for CTL-induced cytolysis of Fas-negative targets. However,
target lysis via the granule exocytosis pathway is completely resistant
to caspase inhibitors. To test the possibility that granzymes trigger a
postcaspase cytoplasmic apoptotic pathway leading to lysis, we have
examined the caspase dependence of several cytoplasmic changes
associated with apoptotic death. Rapid prelytic phosphatidylserine
externalization was induced in Jurkat target cells by both the Fas
ligand (FasL)/Fas and the granule exocytosis effector pathways. This
was specifically blocked by peptide ketone caspase inhibitors
when induced by the former, but not by the latter, pathway. A rapid
prelytic loss of target mitochondrial 
was also induced by both CTL
effector pathways, and this was also specifically blocked by caspase
inhibitors when induced by the FasL/Fas, but not by the granule
exocytosis, pathway. Similarly, target membrane blebbing induced by CTL
via the FasL/Fas, but not via the granule exocytosis, effector pathway
was specifically blocked by caspase inhibitors. In contrast to the
above nonnuclear damage, CTL-induced target staining by the lipid probe
FM1–43 reflecting plasma membrane endocytosis was blocked by caspase
inhibitors. Thus, when caspase activation is blocked, the granule
exocytosis pathway triggers several parameters of target apoptotic
damage in addition to lysis, suggesting that granzymes directly trigger
a postcaspase cytoplasmic apoptotic death
pathway.
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