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.
Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA. morelli@imap.pitt.edu.
Adrian E
AE
Morelli
Adriana T
AT
Larregina
William J
WJ
Shufesky
Mara L G
ML
Sullivan
Donna Beer
DB
Stolz
Glenn D
GD
Papworth
Alan F
AF
Zahorchak
Alison J
AJ
Logar
Zhiliang
Z
Wang
Simon C
SC
Watkins
Louis D
LD
Falo
Angus W
AW
Thomson
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