RRC ID 59831
Author Shimizu K, Yamasaki S, Sakurai M, Yumoto N, Ikeda M, Mishima-Tsumagari C, Kukimoto-Niino M, Watanabe T, Kawamura M, Shirouzu M, Fujii SI.
Title Granzyme A Stimulates pDCs to Promote Adaptive Immunity via Induction of Type I IFN.
Journal Front Immunol
Abstract Granzyme A (GzmA), together with perforin, are well-known for their cytotoxic activity against tumor or virus-infected cells. In addition to this cytotoxic function, GzmA stimulates several immune cell types and induces inflammation in the absence of perforin, however, its effect on the dendritic cell (DC) is unknown. In the current study, we showed that recombinant GzmA induced the phenotypic maturation of plasmacytoid DCs (pDCs) and conventional DCs (cDCs), but not their apoptosis. Particularly, GzmA made pDCs more functional, thus leading to production of type I interferon (IFN) via the TLR9-MyD88 pathway. We also demonstrated that GzmA binds TLR9 and co-localizes with it in endosomes. When co-administered with antigen, GzmA acted as a powerful adjuvant for eliciting antigen-specific cytotoxic CD8+ T lymphocytes (CTLs) that protected mice from tumor challenge. The induction of CTL was completely abolished in XCR1+ DC-depleted mice, whereas it was reduced to less than half in pDC-depleted or IFN-α/β receptor knockout mice. Thus, CTL cross-priming was dependent on XCR1+cDC and also type I IFN, which was produced by GzmA-activated pDCs. These results indicate that GzmA -stimulated pDCs enhance the cross-priming activity of cDCs in situ. We also showed that the adjuvant effect of GzmA is superior to CpG-ODN and LPS. Our findings highlight the ability of GzmA to bridge innate and adaptive immune responses via pDC help and suggest that GzmA may be useful as a vaccine adjuvant.
Volume 10
Pages 1450
Published 2019-1-1
DOI 10.3389/fimmu.2019.01450
PMID 31293597
PMC PMC6606709
MeSH Animals CD8-Positive T-Lymphocytes / cytology CD8-Positive T-Lymphocytes / immunology* Dendritic Cells / cytology Dendritic Cells / immunology* Granzymes / genetics Granzymes / immunology Granzymes / pharmacology* Immunity, Cellular / drug effects* Mice Mice, Knockout Myeloid Differentiation Factor 88 / genetics Myeloid Differentiation Factor 88 / immunology Plasma Cells / cytology Plasma Cells / immunology* Toll-Like Receptor 9 / genetics Toll-Like Receptor 9 / immunology
IF 4.716
Times Cited 2
Human and Animal Cells 293T(RCB2202)