Granzyme B-induced cell death exerted by ex vivo CTL: discriminating requirements for cell death and some of its signs.

Publication Type:

Journal Article

Source:

Cell death and differentiation, Volume 15, Issue 3, p.567-79 (2008)

Keywords:

Animals, APOPTOSIS, Apoptosis Regulatory Proteins, Caspase 3, Caspase 7, Cell Membrane, Cell Membrane Permeability, Cells, Cultured, Cytochromes c, Granzymes, Membrane Potential, Mitochondrial, MICE, Mice, Knockout, Phosphatidylserines, Reactive Oxygen Species, T-Lymphocytes, Cytotoxic

Abstract:

Granzyme B (gzmB) of cytotoxic T lymphocytes (CTL) is essential for recovery from intracellular pathogens, but the molecular basis of its action is still unresolved. Here, we analyzed gzmB-mediated death pathways under physiological conditions using ex vivo virus-immune CTLs that express perf and gzmB, but not gzmA (gzmB(+)CTL). We show that gzmB(+)CTL abrogate target cell proliferation most likely by inducing cell death, independent of caspases and mitochondrial signaling. In addition, the data reveal that gzmB(+)CTL independently induce pro-apoptotic processes either via caspase-3/-7, leading to plasma membrane perturbance and ROS production or via Bid/Bak/Bax, resulting in cytochrome c release and that both pathways elicit loss of DeltaPsi(m). Our data provide evidence for a pleiotropic pro-apoptotic function of gzmB presumably to counteract evasion strategies of pathogens and to control tumors.