Submitted August 3, 2007
Accepted December 13, 2007
Cytotoxic T lymphocytes overcome Bcl-2 inhibition: target cells contribute to their own demise
Ing Swie Goping, Tracy Sawchuk, Aja Rieger, Irene Shostak, and R. Chris Bleackley*
Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
* Corresponding author; email: chris.bleackley{at}ualberta.ca.
Cytotoxic T lymphocytes (CTL) 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, CTL 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 CTL 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 CTL and importantly, inhibition of this directed movement attenuates killing. Therefore we propose that CTL initiate a target cell response which activates multiple mitochondrial pathways. This ensures that CTL can eliminate those target cells that have compromised apoptotic potential due to over-expression of Bcl-2.
