1. ¹Metschnikoff Laboratory, Max-Planck-Institut für Immunbiologie, Freiburg, Germany
2. ²Dpto. Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Zaragoza, Spain
3. ³Institut für Immunologie, Universitätsklinikum Heidelberg, Heidelberg, Germany
4. ⁴Institute of Molecular Medicine and Cell Research, Center for Biochemistry and Molecular Research, Freiburg, Germany
5. ⁵Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
6. ⁶Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA
7. ⁷Viral Immunology, Division of Immunology and Genetics, John Curtin School of Medical Research, Australian National University, Canberra, Australia

Correspondence: MM Simon, Metschnikoff Laboratory, Max-Planck-Institut für Immunbiologie, Stübeweg 51, Freiburg, Germany. Tel: +49 761 5108 533; Fax: +49 761 5108 529; E-mail: simon@immunbio.mpg.de

Received 8 May 2007; Revised 20 September 2007; Accepted 29 October 2007; Published online 7 December 2007.

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 _m. Our data provide evidence for a pleiotropic pro-apoptotic function of gzmB presumably to counteract evasion strategies of pathogens and to control tumors.