TY - JOUR
T1 - Exosomes as a short-range mechanism to spread alloantigen between dendritic cells during T cell allorecognition
AU - Montecalvo, Angela
AU - Shufesky, William J.
AU - Stolz, Donna Beer
AU - Sullivan, Mara G.
AU - Wang, Zhiliang
AU - Divito, Sherrie J.
AU - Papworth, Glenn D.
AU - Watkins, Simon C.
AU - Robbins, Paul D.
AU - Larregina, Adriana T.
AU - Morelli, Adrian E.
PY - 2008/3/1
Y1 - 2008/3/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=49149111236&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.180.5.3081
DO - 10.4049/jimmunol.180.5.3081
M3 - Article
C2 - 18292531
AN - SCOPUS:49149111236
SN - 0022-1767
VL - 180
SP - 3081
EP - 3090
JO - Journal of Immunology
JF - Journal of Immunology
IS - 5
ER -