title: A critical role for granzymes in antigen cross-presentation through regulating phagocytosis of killed tumor cells.
abstract: Granzymes A and B (GrAB) are known principally for their role in mediating perforin-dependent death of virus-infected or malignant cells targeted by CTL. In this study, we show that granzymes also play a critical role as inducers of Ag cross-presentation by dendritic cells (DC). This was demonstrated by the markedly reduced priming of naive CD8(+) T cells specific for the model Ag OVA both in vitro and in vivo in response to tumor cells killed in the absence of granzymes. Reduced cross-priming was due to impairment of phagocytosis of tumor cell corpses by CD8α(+) DC but not CD8α(-) DC, demonstrating the importance of granzymes in inducing the exposure of prophagocytic "eat-me" signals on the dying target cell. Our data reveal a critical and previously unsuspected role for granzymes A and B in dictating immunogenicity by influencing the mode of tumor cell death and indicate that granzymes contribute to the efficient generation of immune effector pathways in addition to their well-known role in apoptosis induction.
authors.affiliation: Cancer Cell Death Laboratory, Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3002, Victoria, Australia. sabine.hoves@web.de
authors.forename: Sabine
authors.initials: S
authors.lastname: Hoves
authors.forename: Vivien R
authors.initials: VR
authors.lastname: Sutton
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Haynes
authors.forename: Edwin D
authors.initials: ED
authors.lastname: Hawkins
authors.forename: Daniel
authors.initials: D
authors.lastname: Fernández Ruiz
authors.forename: Nikola
authors.initials: N
authors.lastname: Baschuk
authors.forename: Karin A
authors.initials: KA
authors.lastname: Sedelies
authors.forename: Maximilian
authors.initials: M
authors.lastname: Schnurr
authors.forename: John
authors.initials: J
authors.lastname: Stagg
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Andrews
authors.forename: Jose A
authors.initials: JA
authors.lastname: Villadangos
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Trapani
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism*; D016923:Cell Death / Q000276:immunology; D045744:Cell Line, Tumor; D002645:Chickens; D045142:Cross-Priming / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D053804:Granzymes / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000633:toxicity; D010446:Peptide Fragments / Q000633:toxicity; D010587:Phagocytosis / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*
chemical_list: D000951:Antigens, Neoplasm; C110366:OVA-8; D010446:Peptide Fragments; D010047:Ovalbumin; C509213:GZMB protein, human; D053804:Granzymes; C509214:Gzmb protein, mouse