Exosomes as potent cell-free peptide-based vaccine. I. Dendritic cell-derived exosomes transfer functional MHC class I/peptide complexes to dendritic cells.
Current immunization protocols in cancer patients involve CTL-defined tumor peptides. Mature dendritic cells (DC) are the most potent APCs for the priming of naive CD8(+) T cells, eventually leading to tumor eradication. Because DC can secrete MHC class I-bearing exosomes, we addressed whether exosomes pulsed with synthetic peptides could subserve the DC function consisting in MHC class I-restricted, peptide-specific CTL priming in vitro and in vivo. The priming of CTL restricted by HLA-A2 molecules and specific for melanoma peptides was performed: 1) using in vitro stimulations of total blood lymphocytes with autologous DC pulsed with GMP-manufactured autologous exosomes in a series of normal volunteers; 2) in HLA-A2 transgenic mice (HHD2) using exosomes harboring functional HLA-A2/Mart1 peptide complexes. In this study, we show that: 1). DC release abundant MHC class I/peptide complexes transferred within exosomes to other naive DC for efficient CD8(+) T cell priming in vitro; 2). exosomes require nature's adjuvants (mature DC) to efficiently promote the differentiation of melanoma-specific effector T lymphocytes producing IFN-gamma (Tc1) effector lymphocytes in HLA-A2 transgenic mice (HHD2). These data imply that exosomes might be a transfer mechanism of functional MHC class I/peptide complexes to DC for efficient CTL activation in vivo.
André
Fabrice
F
Unité d'Immunologie, ERM0208 Institut National de la Santé et de la Recherche Médicale, Department of Clinical Biology, Institut Gustave Roussy, Villejuif, France.
Chaput
Nathalie
N
Schartz
Nöel E C
NE
Flament
Caroline
C
Aubert
Nathalie
N
Bernard
Jacky
J
Lemonnier
François
F
Raposo
Graça
G
Escudier
Bernard
B
Hsu
Di-Hwei
DH
Tursz
Thomas
T
Amigorena
Sebastian
S
Angevin
Eric
E
Zitvogel
Laurence
L
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000951:Antigens, Neoplasm; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D002474:Cell-Free System / Q000276:immunology; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism* / Q000637:transplantation; D011992:Endosomes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000276:immunology; D015789:HLA-A2 Antigen / Q000008:administration & dosage / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000008:administration & dosage / Q000276:immunology*; D006801:Humans; D007399:Interphase / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D058965:MART-1 Antigen; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000008:administration & dosage / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000276:immunology*
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D015395:Histocompatibility Antigens Class I; D058965:MART-1 Antigen; C548667:MLANA protein, human; C548668:Mlana protein, mouse; D009363:Neoplasm Proteins; D022223:Vaccines, Subunit