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

• 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
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1001670

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.