Abstract
Extracellular vesicles (EV), including exosomes and microvesicles (MV), represent a rapidly expanding field of research with diagnostic and therapeutic applications. Although many aspects of EV function remain to be revealed and broad investigations are warranted, most published findings focus on only one vesicle category or a non-separated mix of EVs. In this paper, we investigated both MVs and exosomes from Ovalbumin (OVA)-pulsed dendritic cells for their immunostimulatory potential side-by-side in vivo. Only exosomes induced antigen-specific CD8+ T-cells, and were more efficient than MVs in eliciting antigen-specific IgG production. Further, mainly exosome-primed mouse splenocytes showed significant ex vivo interferon gamma production in response to antigen restimulation. Exosomes carried high levels of OVA, while OVA in MVs was barely detectable, which could explain the more potent antigen-specific response induced by exosomes. Moreover, exosomes induced increased germinal center B cell proportions, whereas MVs had no such effect. Immunisation with both vesicle types combined showed neither inhibitory nor synergistic effects. We conclude that DC-derived MVs and exosomes differ in their capacity to incorporate antigen and induce immune responses. The results are of importance for understanding the role of EVs in vivo, and for future design of vesicle-based immunotherapies and vaccines.
Highlights
Extracellular vesicles (EV) have been studied as drug delivery vehicles, vaccine- and immune therapy tools and as carriers of biomarkers[1,2,3]
We have previously shown that strong Th1-skewed[13] immune responses are induced by dendritic cells (DC)-Exo in mice, where the T cell response is B cell-dependent[13,14]
Quantifications based on mean fluorescence intensity for four batches of EVs showed OVA-pulsing had no significant effect on the expressions of the markers analysed (Fig. 1 and histogram-based overview in Supplementary Fig. S1)
Summary
Extracellular vesicles (EV) have been studied as drug delivery vehicles, vaccine- and immune therapy tools and as carriers of biomarkers[1,2,3]. Exosomes from dendritic cells (DC) were later shown to carry CD54, CD86 and MHC class I and II9 and to be able to induce antigen-specific tumour regression in a murine cancer model[10]. We have shown that T- and B cell responses to exosomes in vivo are mainly dependent on the presence of whole OVA antigen rather than MHC-peptide on the exosomes[15]. In the present paper we have, for the first time, investigated the in vivo immunostimulatory effects of exosomes and MVs derived from the same antigen-pulsed DCs, as a model for EV-based therapy. We found that exosomes and MVs differ greatly in capacity to incorporate exogenous antigen and to induce cellular and humoral immune responses in vivo
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