ABSTRACT
The use of live Listeria-based vaccines carries serious difficulties when administrated to immunocompromised individuals. However, cellular carriers have the advantage of inducing multivalent innate immunity as well as cell-mediated immune responses, constituting novel and secure vaccine strategies in listeriosis. Here, we compare the protective efficacy of dendritic cells (DCs) and macrophages and their safety. We examined the immune response of these vaccine vectors using two Listeria antigens, listeriolysin O (LLO) and glyceraldehyde-3-phosphate-dehydrogenase (GAPDH), and several epitopes such as the LLO peptides, LLO189-201 and LLO91-99 and the GAPDH peptide, GAPDH1-22. We discarded macrophages as safe vaccine vectors because they show anti-Listeria protection but also high cytotoxicity. DCs loaded with GAPDH1-22 peptide conferred higher protection and security against listeriosis than the widely explored LLO91-99 peptide. Anti-Listeria protection was related to the changes in DC maturation caused by these epitopes, with high production of interleukin-12 as well as significant levels of other Th1 cytokines such as monocyte chemotactic protein-1, tumor necrosis factor-α, and interferon-γ, and with the induction of GAPDH1-22-specific CD4(+) and CD8(+) immune responses. This is believed to be the first study to explore the use of a novel GAPDH antigen as a potential DC-based vaccine candidate for listeriosis, whose efficiency appears to highlight the relevance of vaccine designs containing multiple CD4(+) and CD8(+) epitopes.
Subject(s)
Antigens, Bacterial/immunology , Bacterial Vaccines/adverse effects , Bacterial Vaccines/immunology , Dendritic Cells/immunology , Glyceraldehyde-3-Phosphate Dehydrogenases/immunology , Listeria/immunology , Listeriosis/prevention & control , Animals , Bacterial Toxins/immunology , Bacterial Vaccines/administration & dosage , Cytokines/metabolism , Heat-Shock Proteins/immunology , Hemolysin Proteins/immunology , Listeria/enzymology , Macrophages/immunology , Mice , Mice, Inbred C57BLABSTRACT
Phagosomes are critical compartments for innate immunity. However, their role in the protection against murine listeriosis has not been examined. We describe here that listericidal phago-receptosomes are induced by the function of IFN-γ or IL-6 as centralized compartments for innate and adaptive immunity because they are able to confer protection against murine listeriosis. These phago-receptosomes elicited LLO(91-99)/CD8(+)- and LLO(189-201)/CD4(+)-specific immune responses and recruited mature dendritic cells to the vaccination sites controlled by T cells. Moreover, they present exceptional features as efficient vaccine vectors. First, they compartmentalize a novel listericidal STAT-1-mediated signaling pathway that confines multiple innate immune components to the same environment. Second, they show features of MHC class II antigen-loading competent compartments for cathepsin-D-mediated LLO processing. Third, murine cathepsin-D deficiencies fail to develop protective immunity after vaccination with listericidal phago-receptosomes induced by IFN-γ or IL-6. Therefore, it appears that the connection of STAT-1 and cathepsin-D in a single compartment is relevant for protection against listeriosis.
Subject(s)
Bacterial Vaccines/immunology , Cathepsin D/immunology , Dendritic Cells/metabolism , Interferon-gamma/immunology , Interleukin-6/immunology , Listeria monocytogenes/immunology , Listeriosis/immunology , Phagosomes/immunology , STAT1 Transcription Factor/immunology , Animals , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Cathepsin D/genetics , Cathepsin D/metabolism , Dendritic Cells/immunology , Histocompatibility Antigens Class II/genetics , Histocompatibility Antigens Class II/immunology , Histocompatibility Antigens Class II/metabolism , Interferon-gamma/genetics , Interferon-gamma/metabolism , Interleukin-6/genetics , Interleukin-6/metabolism , Listeria monocytogenes/metabolism , Listeriosis/genetics , Listeriosis/metabolism , Listeriosis/prevention & control , Mice , Mice, Knockout , Phagosomes/genetics , Phagosomes/metabolism , STAT1 Transcription Factor/genetics , STAT1 Transcription Factor/metabolism , Signal Transduction/genetics , Signal Transduction/immunologyABSTRACT
LLO is the major immuno-dominant antigen in listeriosis and is also required for protective immunity. Two forms of LLO can be observed in endosomal membranes, a LLO intact form and a Ctsd-processed LLO(1-491) form. Endosomes obtained from resting macrophages contained only LLO intact forms, while endosomes obtained from IFN-activated macrophages contained both forms. Both types of endosomes elicited LLO(90-91)/CD8(+) and LLO(189-201)/CD4(+) specific immune responses. However, only endosomes containing the Ctsd-processed LLO(1-491) form showed significant CD4(+) and CD8(+) T cell responses similar to LM infected bone marrow derived macrophages and characteristic of protective Listeria immunity. Moreover, endosomes with intact LLO could not confer protection as vaccine carriers against murine listeriosis. While endosomes with Ctsd-processed LLO(1-491) form showed a moderate ability, slightly lower than high efficiency vaccine vectors as MØ infected with LM. These studies argue that all cell-free membrane vesicles might serve as valid vaccine carriers against infectious agents. Exclusively those cell-free vesicles MIIC competent for LLO processing are protective vaccines vectors since they recruit significant numbers of mature dendritic cells to the vaccination sites and contain a LLO(1-491) form that might be accessible for MHC class I and class II antigen presentation.
