Journal
BLOOD
Volume 104, Issue 10, Pages 3257-3266Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2004-03-0824
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Funding
- NCI NIH HHS [R01 CA100893, P01 CA73743] Funding Source: Medline
- NHLBI NIH HHS [R21 HL69725] Funding Source: Medline
- NIAID NIH HHS [R21 AI55027, R21 AI57958, R01 AI43916, R01 AI41011] Funding Source: Medline
- NIDDK NIH HHS [R01 DK49745] Funding Source: Medline
- PHS HHS [R01 075512] Funding Source: Medline
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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 IAb 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. (C) 2004 by The American Society of Hematology.
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