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Endocytosis, intracellular sorting, and processing of exosomes by dendritic cells
Abstract
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 αv/β3 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 IEα52-68 in IAb by host CD8α+ 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.
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Metadata
- Authors
- Morelli, A. E., Larregina, A. T., Shufesky, W. J., Sullivan, M. L. G., Stolz, D. B., Papworth, G. D., Zahorchak, A. F., Logar, A. J., Wang, Z., Watkins, S. C., Falo, L. D., & Thomson, A. W.
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2004-11-15
- Volume
- 104
- Issue
- 10
- Pages
- 3257-3266
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2123614057
- Cited by
- 1,073
- References
- 2
- FWCI
- 7.11
- Type
- journal article
- Language
- en
- Open access
- closed
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