Pardo J, Wallich R, Martin P, Urban C, Rongvaux A, Flavell R A, Müllbacher A, Borner C, Simon M M
Metschnikoff Laboratory, Max-Planck-Institut für Immunbiologie, Freiburg, Germany.
Cell Death Differ. 2008 Mar;15(3):567-79. doi: 10.1038/sj.cdd.4402289. Epub 2007 Dec 7.
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.
细胞毒性T淋巴细胞（CTL）的颗粒酶B（gzmB）对于从细胞内病原体感染中恢复至关重要，但其作用的分子基础仍未阐明。在此，我们使用表达穿孔素（perforin）和gzmB但不表达gzmA的离体病毒免疫CTL（gzmB(+)CTL），分析了生理条件下gzmB介导的死亡途径。我们发现，gzmB(+)CTL最有可能通过诱导细胞死亡来消除靶细胞增殖，这一过程不依赖于半胱天冬酶和线粒体信号传导。此外，数据显示gzmB(+)CTL通过半胱天冬酶-3/-7独立诱导促凋亡过程，导致质膜扰动和活性氧生成，或者通过Bid/Bak/Bax诱导促凋亡过程，导致细胞色素c释放，并且这两条途径都会引起线粒体膜电位（ΔΨm）的丧失。我们的数据为gzmB的多效性促凋亡功能提供了证据，推测该功能可对抗病原体的逃避策略并控制肿瘤。
