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* Unité d’Immunologie, ERM0208 Institut National de la Santé et de la Recherche Médicale, Department of Clinical Biology, Institut Gustave Roussy, Villejuif, France;
Unité Mixte de Recherche 144 Centre National de la Recherche Scientifique Institut Curie, Paris, France;
Centre Jean Godinot, Reims, France;
Unité d’Immunologie Cellulaire Antivirale, Institut Pasteur, Paris, France;
¶ Service de Dermatologie 2, AP-HP Saint Louis, Paris, France;
|| Institut National de la Santé et de la Recherche Médicale Unité 520, Institut Curie, Paris, France; and
# Anosys, Inc., Menlo Park, CA 94025.
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-
(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.
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