CASPASE DEPENDENCE OF TARGET-CELL DAMAGE-INDUCED BY CYTOTOXIC LYMPHOCYTES

Citation
A. Sarin et al., CASPASE DEPENDENCE OF TARGET-CELL DAMAGE-INDUCED BY CYTOTOXIC LYMPHOCYTES, The Journal of immunology (1950), 161(6), 1998, pp. 2810-2816
Citations number
51
Categorie Soggetti
Immunology
ISSN journal
00221767
Volume
161
Issue
6
Year of publication
1998
Pages
2810 - 2816
Database
ISI
SICI code
0022-1767(1998)161:6<2810:CDOTDB>2.0.ZU;2-Z
Abstract
Since the CTL secreted granule protease granzyme B can activate multip le target caspases, it has been proposed that this pathway is responsi ble for CTL-induced cytolysis of Fas-negative targets. However, target lysis via the granule exocytosis pathway is completely resistant to c aspase inhibitors. To test the possibility that granzymes trigger a po stcaspase cytoplasmic apoptotic pathway leading to lysis, we have exam ined the caspase dependence of several cytoplasmic changes associated with apoptotic death. Rapid prelytic phosphatidylserine externalizatio n was induced in Jurkat target cells by both the Fas ligand (FasL)/Fas and the granule exocytosis effector pathways, This was specifically b locked by peptide ketone caspase inhibitors when induced by the former , but not by the latter, pathway. A rapid prelytic loss of target mito chondrial psi was also induced by both CTL effector pathways, and this was also specifically blocked by caspase inhibitors when induced by t he FasL/Fas, but not by the granule exocytosis, pathway. Similarly, ta rget membrane blebbing induced by CTL via the FasL/Fas, but not via th e granule exocytosis, effector pathway was specifically blocked by cas pase inhibitors. In contrast to the above nonnuclear damage, CTL-induc cd target staining by the lipid probe FM1-43 reflecting plasma membran e endocytosis was blocked by caspase inhibitors. Thus, when caspase ac tivation is blocked, the granule exocytosis pathway triggers several p arameters of target apoptotic damage in addition to lysis, suggesting that granzymes directly trigger a postcaspase cytoplasmic apoptotic de ath pathway.