Exosomes as a short-range mechanism to spread alloantigen between dendritic cells during T cell allorecognition.
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.
Montecalvo
Angela
A
Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213-2582, USA.
Shufesky
William J
WJ
Stolz
Donna Beer
DB
Sullivan
Mara G
MG
Wang
Zhiliang
Z
Divito
Sherrie J
SJ
Papworth
Glenn D
GD
Watkins
Simon C
SC
Robbins
Paul D
PD
Larregina
Adriana T
AT
Morelli
Adrian E
AE
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D022162:Cytoplasmic Vesicles / Q000276:immunology* / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D016027:Heart Transplantation / Q000276:immunology; D007519:Isoantigens / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016038:Skin Transplantation / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*
D007519:Isoantigens