A critical role for granzymes in antigen cross-presentation through regulating phagocytosis of killed tumor cells

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 demonstrate...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2011-08, Vol.187 (3), p.1166-1175
Main Authors: Hoves, Sabine, Sutton, Vivien R, Haynes, Nicole M, Hawkins, Edwin D, Fernández Ruiz, Daniel, Baschuk, Nikola, Sedelies, Karin A, Schnurr, Maximilian, Stagg, John, Andrews, Daniel M, Villadangos, Jose A, Trapani, Joseph A
Format: Article
Language:English
Subjects:
Animals
Antigens, Neoplasm - immunology
Antigens, Neoplasm - metabolism
Cell Death - immunology
Cell Line, Tumor
Chickens
Cross-Priming - immunology
Dendritic Cells - immunology
Dendritic Cells - metabolism
Granzymes - deficiency
Granzymes - genetics
Granzymes - physiology
Humans
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Ovalbumin - toxicity
Peptide Fragments - toxicity
Phagocytosis - immunology
T-Lymphocytes, Cytotoxic - enzymology
T-Lymphocytes, Cytotoxic - immunology
T-Lymphocytes, Cytotoxic - pathology
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Summary: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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1001670