Granzyme B-induced cell death exerted by ex vivo CTL: discriminating requirements for cell death and some of its signs.
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.
Pardo
J
J
Metschnikoff Laboratory, Max-Planck-Institut für Immunbiologie, Freiburg, Germany.
Wallich
R
R
Martin
P
P
Urban
C
C
Rongvaux
A
A
Flavell
R A
RA
Müllbacher
A
A
Borner
C
C
Simon
M M
MM
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D053804:Granzymes / Q000235:genetics / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D018345:Mice, Knockout; D010718:Phosphatidylserines / Q000032:analysis; D017382:Reactive Oxygen Species / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology* / Q000276:immunology
D051017:Apoptosis Regulatory Proteins; D010718:Phosphatidylserines; D017382:Reactive Oxygen Species; D045304:Cytochromes c; D053804:Granzymes; C509214:Gzmb protein, mouse; D053148:Caspase 3; D053179:Caspase 7