title: Mouse cytotoxic T cell-derived granzyme B activates the mitochondrial cell death pathway in a Bim-dependent fashion.
abstract: Cytotoxic T cells (Tc) use perforin and granzyme B (gzmB) to kill virus-infected cells and cancer cells. Recent evidence suggests that human gzmB primarily induces apoptosis via the intrinsic mitochondrial pathway by either cleaving Bid or activating Bim leading to the activation of Bak/Bax and subsequent generation of active caspase-3. In contrast, mouse gzmB is thought to predominantly induce apoptosis by directly processing pro-caspase-3. However, in certain mouse cell types gzmB-mediated apoptosis mainly occurs via the mitochondrial pathway. To investigate whether Bim is involved under the latter conditions, we have now employed ex vivo virus-immune mouse Tc that selectively kill by using perforin and gzmB (gzmB(+)Tc) as effector cells and wild type as well as Bim- or Bak/Bax-deficient spontaneously (3T9) or virus-(SV40) transformed mouse embryonic fibroblast cells as targets. We show that gzmB(+)Tc-mediated apoptosis (phosphatidylserine translocation, mitochondrial depolarization, cytochrome c release, and caspase-3 activation) was severely reduced in 3T9 cells lacking either Bim or both Bak and Bax. This outcome was related to the ability of Tc cells to induce the degradation of Mcl-1 and Bcl-XL, the anti-apoptotic counterparts of Bim. In contrast, gzmB(+)Tc-mediated apoptosis was not affected in SV40-transformed mouse embryonic fibroblast cells lacking Bak/Bax. The data provide evidence that Bim participates in mouse gzmB(+)Tc-mediated apoptosis of certain targets by activating the mitochondrial pathway and suggest that the mode of cell death depends on the target cell. Our results suggest that the various molecular events leading to transformation and/or immortalization of cells have an impact on their relative resistance to the multiple gzmB(+)Tc-induced death pathways.
authors.affiliation: From the Departamento Bioquímica y Biología Molecular y Celular, Biomedical Research Centre of Aragon, IIS Aragon, and.
authors.forename: Elena
authors.initials: E
authors.lastname: Catalán
authors.affiliation: From the Departamento Bioquímica y Biología Molecular y Celular, Biomedical Research Centre of Aragon, IIS Aragon, and.
authors.forename: Paula
authors.initials: P
authors.lastname: Jaime-Sánchez
authors.affiliation: Departamento Microbiología, Medicina Preventiva y Salud Publica, Universidad de Zaragoza, 50009 Zaragoza, Spain.
authors.forename: Nacho
authors.initials: N
authors.lastname: Aguiló
authors.affiliation: the Metschnikoff Laboratory, Max-Planck-Institute for Immunology and Epigenetics, 79108 Freiburg, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Simon
authors.affiliation: the NorthShore University Health Systems Research Institute, University of Chicago, Evanston, Illinois 60201.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Froelich
authors.affiliation: From the Departamento Bioquímica y Biología Molecular y Celular, Biomedical Research Centre of Aragon, IIS Aragon, and Departamento Microbiología, Medicina Preventiva y Salud Publica, Universidad de Zaragoza, 50009 Zaragoza, Spain, the Nanoscience Institute of Aragon, University of Zaragoza, 50015 Zaragoza, Spain, and the Aragon I+D Foundation, 50015 Zaragoza, Spain pardojim@unizar.es.
authors.forename: Julián
authors.initials: J
authors.lastname: Pardo
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology*; D000072224:Bcl-2-Like Protein 11; D053148:Caspase 3 / Q000276:immunology; D002460:Cell Line; D005347:Fibroblasts / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D017353:Gene Deletion; D053804:Granzymes / Q000276:immunology*; D007167:Immunotherapy; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008928:Mitochondria / Q000276:immunology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000276:immunology / Q000378:metabolism; D009369:Neoplasms / Q000628:therapy; D052899:Pore Forming Cytotoxic Proteins / Q000276:immunology; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology* / Q000276:immunology
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C579094:Mcl1 protein, mouse; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D052899:Pore Forming Cytotoxic Proteins; D011518:Proto-Oncogene Proteins; C483886:perforin, mouse; D053804:Granzymes; D053148:Caspase 3
keywords: Apoptosis; B Cell Lymphoma 2 (Bcl-2) Family; Cancer; Cancer Therapy; Immunotherapy; T Cell