Endocytosis, intracellular sorting, and processing of exosomes by dendritic cells

被引:825
作者
Morelli, AE
Larregina, AT
Shufesky, WJ
Sullivan, MLG
Stolz, DB
Papworth, GD
Zahorchak, AF
Logar, AJ
Wang, ZL
Watkins, SC
Falo, LD
Thomson, AW
机构
[1] Univ Pittsburgh, Inst Canc, Thomas E Starzl Transplantat Inst, Pittsburgh, PA USA
[2] Univ Pittsburgh, Inst Canc, Dept Surg, Pittsburgh, PA USA
[3] Univ Pittsburgh, Inst Canc, Dept Dermatol, Pittsburgh, PA USA
[4] Univ Pittsburgh, Med Ctr, Ctr Biol Imaging, Pittsburgh, PA USA
[5] Univ Pittsburgh, Med Ctr, Dept Immunol, Pittsburgh, PA USA
[6] Univ Pittsburgh, Med Ctr, Dept Cell Biol, Pittsburgh, PA USA
[7] Univ Pittsburgh, Med Ctr, Ctr Biol Imaging, Pittsburgh, PA USA
关键词
D O I
10.1182/blood-2004-03-0824
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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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页码:3257 / 3266
页数:10
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