Abstract
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.
Highlights
The effectiveness of phagosomes as vaccines is unknown
We evaluated the activation of these cells when exposed to pro-inflammatory cytokines that are involved in L. monocytogenes immune responses (i.e. TNF-␣, IFN-␥, IL-6, IL-10, and IL-12)
Similar results were obtained using a cathepsin-D inhibitor, pepstatin A, further supporting the participation of CTSD in L. monocytogenes degradation [15]. These results suggest that IFN-␥ and IL-6 induce similar oxidative and nonoxidative listericidal mechanisms in J-774 cells and that TNF-␣ does not mediate phagosomal L. monocytogenes degradation controlled by lysosomal proteases (Fig. 1C)
Summary
The effectiveness of phagosomes as vaccines is unknown. Results: Listericidal phagosomes contain a compartmentalized signaling pathway and a nontoxic listeriolysin form bound to immune molecules. We describe here that listericidal phago-receptosomes are induced by the function of IFN-␥ 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. We examine the hypothesis that a common listericidal route induced by pro-inflammatory cytokines may be compartmentalized in unique vesicles connecting STAT-mediated signaling, trafficking regulators, listericidal lysosomal enzymes such as CTSD, and immune phagosomal functions. Our approach involved the use of differential gene expression methods combined with basic proteomic, functional analyses of L. monocytogenes phagosomes, and their use as vaccine vectors against listeriosis All these studies were verified using MØs genetically deficient in putative upstream components of this signaling route such as STAT-1 and STAT-3 and the postulated downstream lysosomal component CTSD. We describe a novel phagosomal compartment, the listericidal phago-receptosomes induced by IFN-␥ or IL-6, which may be important Listeria-induced immune vesicles that regulate IL-6 production and constitute effective vaccines to confer protection against listeriosis
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