Differential activation of the death receptor pathway in human target cells induced by cytotoxic T lymphocytes showing different kinetics of killing.
OBJECTIVE
Cytotoxic T lymphocytes (CTL) may use two effector mechanisms to kill their target cells: perforin (PFN) and granzyme B (GrB)-dependent granule-mediated cell death and death receptor-mediated cell death. Controversy exists whether, in addition to PFN/GrB-mediated apoptosis, death receptor-induced apoptosis contributes to the elimination of human tumor cells by CTL.


METHODS
Since the two CTL-mediated effector mechanisms differ in time required to eliminate target cells, lysis of target cells was analyzed using CTL clones with slow and rapid kinetics of killing derived from a patient with chronic myeloid leukemia. To determine the involvement of the death receptor pathway, a retroviral construct encoding the antiapoptotic gene FLICE inhibitory protein (FLIP) was introduced into these target cells.


RESULTS
A CTL clone capable of killing 50% of the target cells within 2 hours of incubation primarily acted by release of PFN and GrB. In contrast, two CTL clones showing slower target cell killing kinetics partially used the death receptor pathway (approximately 30% inhibition by FLIP).


CONCLUSIONS
We demonstrated that the death receptor pathway contributes to T-cell-mediated cell death if not all target cells are destroyed by release of PFN and GrB.
de Vries
Jeltje F
JF
Department of Hematology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. j.f.vries@lumc.nl
von dem Borne
Peter A
PA
van Luxemburg-Heijs
Simone A P
SA
Heemskerk
Mirjam H M
MH
Willemze
Roel
R
Falkenburg
J H Frederik
JH
Barge
Renèe M Y
RM
D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000276:immunology; D053181:Caspase 8 / Q000276:immunology; D061945:Caspase Inhibitors; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D053804:Granzymes / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics / Q000276:immunology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000276:immunology*; D054353:Perforin / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology; D012190:Retroviridae; D013601:T-Lymphocytes / Q000276:immunology*; D013997:Time Factors; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D061945:Caspase Inhibitors; D018124:Receptors, Tumor Necrosis Factor; D054353:Perforin; D053804:Granzymes; C505530:CASP8 protein, human; D053181:Caspase 8