Exosomes As a Short-Range Mechanism to Spread Alloantigen between Dendritic Cells during T Cell Allorecognition

Abstract

Exosomes are nanovesicles released by different cell types including dendritic cells (DCs). The fact that exosomes express surface MHC-peptide complexes suggests that they could function as Ag-presenting vesicles or as vehicles to spread allogeneic Ags for priming of anti-donor T cells during elicitation of graft rejection or induction/maintenance of transplant tolerance. We demonstrate that circulating exosomes transporting alloantigens are captured by splenic DCs of different lineages. Internalization of host-derived exosomes transporting allopeptides by splenic DCs leads to activation of anti-donor CD4 T cells by the indirect pathway of allorecognition, a phenomenon that requires DC-derived, instead of exosome-derived, MHC class II molecules. By contrast, allogeneic exosomes are unable to stimulate direct-pathway T cells in vivo. We demonstrate in mice that although graft-infiltrating leukocytes release exosomes ex vivo, they do not secrete enough concentrations of exosomes into circulation to stimulate donor-reactive T cells in secondary lymphoid organs. Instead, our findings indicate that migrating DCs (generated in vitro or isolated from allografts), once they home in the spleen, they transfer exosomes expressing the reporter marker GFP to spleen-resident DCs. Our results suggest that exchange of exosomes between DCs in lymphoid organs might constitute a potential mechanism by which passenger leukocytes transfer alloantigens to recipient’s APCs and amplify generation of donor-reactive T cells following transplantation.

Functional delivery of viral miRNAs via exosomes

“…Dendritic cells (DC) control T-cell-mediated immunity of EBV infection and control EBVdriven transformation (21,22). In addition, DC modulate adaptive immune responses by internalizing exosomes (23,24). To monitor whether exosomes transfer to primary immature monocyte-derived DC (MoDC), we labeled purified LCL exosomes with a green fluorescent lipid dye (PKH67) that could be made visible with confocal microscopy through capture by HLA-DR-coated beads ( Fig.…”

Exosomes in Viral Disease

“…Once in the extracellular space, exosomes can bind to neighboring cells, bind locally, travel passively through the bloodstream for a more paracrine destination, or be taken up by marginal zone phagocytes in the spleen and liver [4,47].…”

Dendritic Cell–Derived Exosomes as Immunotherapies in the Fight against Cancer

“…2) (4, 26, 27), and this is likely to be the most fundamental pathway in vivo. Of particular note, it was shown that Dex priming of naive T cells can only occur if APCs are present (27)(28)(29). Two key mechanisms have been described for how antigenic peptide-MHC containing Dex could elicit indirect Ag presentation to T cells via an APC.…”