title: Cytotoxic T lymphocytes overcome Bcl-2 inhibition: target cells contribute to their own demise.
abstract: Cytotoxic T lymphocytes (CTLs) eliminate pathogenic cells in large part through the activity of the serine protease granzyme B (grB). However, while the apoptotic activity of grB is blocked by over-expression of Bcl-2, CTLs can still kill target cells through an ill-defined Bcl-2-independent pathway. In this report, we have identified key modulators of this Bcl-2-independent cell-death pathway, which is induced by CTLs and not purified components. Surprisingly, activation of this pathway is reliant on grB. Furthermore, this novel pathway requires mitochondrial contribution through triggering of permeability transition and generation of reactive oxygen species, yet is functional in the absence of Bax/Bak. This pathway stimulates movement of target cell mitochondria toward the point of contact with the CTLs and importantly, inhibition of this directed movement attenuates killing. Therefore, we propose that CTLs initiate a target cell response that activates multiple mitochondrial pathways. This ensures that CTLs can eliminate those target cells that have compromised apoptotic potential due to overexpression of Bcl-2.
authors: Department of Biochemistry, University of Alberta, Edmonton, AB, Canada.
authors: Ing Swie
authors: IS
authors: Goping
authors: Tracy
authors: T
authors: Sawchuk
authors: Aja
authors: A
authors: Rieger
authors: Irene
authors: I
authors: Shostak
authors: R Chris
authors: RC
authors: Bleackley
mesh_terms: D000818:Animals; D017209:Apoptosis; D016923:Cell Death / Q000502:physiology*; D002460:Cell Line; D053804:Granzymes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D007668:Kidney; D051379:Mice; D008810:Mice, Inbred C57BL; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics*; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology*; D014162:Transfection
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D053804:Granzymes