Differential activation of the death receptor pathway in human target cells induced by cytotoxic T lymphocytes showing different kinetics of killing

J. F. de Vries, P. A. von dem Borne, S. A.P. van Luxemburg-Heijs, M. H.M. Heemskerk, R. Willemze, J.H. F. Falkenburg, R. M.Y. Barge
2007 Haematologica  
and Objectives 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. Design and Methods Since the two CTL-mediated effector mechanisms differ in time required to eliminate target cells,
more » ... inate 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 anti-apoptotic 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 (~30% inhibition by FLIP). Interpretation and 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.
doi:10.3324/haematol.11308 pmid:18055991 fatcat:6hlcqsveqng6xkjtiho3wtkjqq