Endocytosis, intracellular sorting, and processing of exosomes by dendritic cells.
Exosomes are nanovesicles released by leukocytes and epithelial cells. Although their function remains enigmatic, exosomes are a source of antigen and transfer functional major histocompatibility complex (MHC)-I/peptide complexes to dendritic cells (DCs) for CD8(+) T-cell activation. Here we demonstrate that exosomes also are internalized and processed by immature DCs for presentation to CD4(+) T cells. Endocytosed exosomes are sorted into the endocytic compartment of DCs for processing, followed by loading of exosome-derived peptides in MHC-II molecules for presentation to CD4(+) T cells. Targeting of exosomes to DCs is mediated via milk fat globule (MFG)-E8/lactadherin, CD11a, CD54, phosphatidylserine, and the tetraspanins CD9 and CD81 on the exosome and alpha(v)/beta(3) integrin, and CD11a and CD54 on the DCs. Circulating exosomes are internalized by DCs and specialized phagocytes of the spleen and by hepatic Kupffer cells. Internalization of blood-borne allogeneic exosomes by splenic DCs does not affect DC maturation and is followed by loading of the exosome-derived allopeptide IEalpha(52-68) in IA(b) by host CD8alpha(+) DCs for presentation to CD4(+) T cells. These data imply that exosomes present in circulation or extracellular fluids constitute an alternative source of self- or allopeptides for DCs during maintenance of peripheral tolerance or initiation of the indirect pathway of allorecognition in transplantation.
Morelli
Adrian E
AE
Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA. morelli@imap.pitt.edu.
Larregina
Adriana T
AT
Shufesky
William J
WJ
Sullivan
Mara L G
ML
Stolz
Donna Beer
DB
Papworth
Glenn D
GD
Zahorchak
Alan F
AF
Logar
Alison J
AJ
Wang
Zhiliang
Z
Watkins
Simon C
SC
Falo
Louis D
LD
Thomson
Angus W
AW
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D000954:Antigens, Surface / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004705:Endocytosis / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology; D007275:Injections, Intravenous; D007519:Isoantigens / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010587:Phagocytosis / Q000276:immunology; D021381:Protein Transport / Q000276:immunology; D013154:Spleen / Q000166:cytology
D000954:Antigens, Surface; D007519:Isoantigens