title: Antigen targeting to CD11b+ dendritic cells in association with TLR4/TRIF signaling promotes strong CD8+ T cell responses.
abstract: Deciphering the mechanisms that allow the induction of strong immune responses is crucial to developing efficient vaccines against infectious diseases and cancer. Based on the discovery that the adenylate cyclase from Bordetella pertussis binds to the CD11b/CD18 integrin, we developed a highly efficient detoxified adenylate cyclase-based vector (CyaA) capable of delivering a large variety of Ags to the APC. This vector allows the induction of protective and therapeutic immunity against viral and tumoral challenges as well as against transplanted tumors in the absence of any added adjuvant. Two therapeutic vaccine candidates against human papilloma viruses and melanoma have been developed recently, based on the CyaA vector, and are currently in clinical trials. We took advantage of one of these highly purified vaccines, produced under good manufacturing practice-like conditions, to decipher the mechanisms by which CyaA induces immune responses. In this study, we demonstrate that CyaA binds both human and mouse CD11b(+) dendritic cells (DCs) and induces their maturation, as shown by the upregulation of costimulatory and MHC molecules and the production of proinflammatory cytokines. Importantly, we show that DCs sense CyaA through the TLR4/Toll/IL-1R domain-containing adapter-inducing IFN-β pathway, independent of the presence of LPS. These findings show that CyaA possesses the intrinsic ability to not only target DCs but also to activate them, leading to the induction of strong immune responses. Overall, this study demonstrates that Ag delivery to CD11b(+) DCs in association with TLR4/Toll/IL-1R domain-containing adapter-inducing IFN-β activation is an efficient strategy to promote strong specific CD8(+) T cell responses.
authors.affiliation: Institut Pasteur, Unité de Régulation Immunitaire et Vaccinologie, Paris F-75015, France; INSERM, U1041, Paris F-75015, France; gilles.dadaglio@pasteur.fr claude.leclerc@pasteur.fr.
authors.forename: Gilles
authors.initials: G
authors.lastname: Dadaglio
authors.affiliation: Institut Pasteur, Unité de Régulation Immunitaire et Vaccinologie, Paris F-75015, France; INSERM, U1041, Paris F-75015, France;
authors.forename: Catherine
authors.initials: C
authors.lastname: Fayolle
authors.affiliation: Institut Pasteur, Unité de Régulation Immunitaire et Vaccinologie, Paris F-75015, France; INSERM, U1041, Paris F-75015, France;
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Unité Mixte de Recherche 7355, Université d'Orléans-Centre National de la Recherche Scientifique, Laboratoire Immunologie et Neurogénétique Expérimentales et Moléculaires, Orléans 45071, France;
authors.forename: Bernard
authors.initials: B
authors.lastname: Ryffel
authors.affiliation: Institut Pasteur, Unité de Régulation Immunitaire et Vaccinologie, Paris F-75015, France; INSERM, U1041, Paris F-75015, France;
authors.forename: Marine
authors.initials: M
authors.lastname: Oberkampf
authors.affiliation: Institut Pasteur, Unité de Régulation Immunitaire et Vaccinologie, Paris F-75015, France; INSERM, U1041, Paris F-75015, France;
authors.forename: Tristan
authors.initials: T
authors.lastname: Felix
authors.affiliation: Division of Gene Therapy and Hepatology, Centre for Applied Medical Research, University of Navarra, Pamplona 31008, Spain;
authors.forename: Sandra
authors.initials: S
authors.lastname: Hervas-Stubbs
authors.affiliation: Institute of Microbiology of the Academy of Sciences of the Czech Republic, Verejna Vyzkumna Instituce, Videnska 1083, 142 20 Prague, Czech Republic;
authors.forename: Radim
authors.initials: R
authors.lastname: Osicka
authors.affiliation: Institute of Microbiology of the Academy of Sciences of the Czech Republic, Verejna Vyzkumna Instituce, Videnska 1083, 142 20 Prague, Czech Republic;
authors.forename: Peter
authors.initials: P
authors.lastname: Sebo
authors.affiliation: Institut Pasteur, Unité de Biochimie des Interactions Macromoléculaires, Paris F-75015, France; and Centre National de la Recherche Scientifique, Unité Mixte de Recherche 3528, Paris F-75015, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ladant
authors.affiliation: Institut Pasteur, Unité de Régulation Immunitaire et Vaccinologie, Paris F-75015, France; INSERM, U1041, Paris F-75015, France; gilles.dadaglio@pasteur.fr claude.leclerc@pasteur.fr.
authors.forename: Claude
authors.initials: C
authors.lastname: Leclerc
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology*; D037361:Adenylate Cyclase Toxin / Q000276:immunology*; D000818:Animals; D018122:B7-1 Antigen / Q000096:biosynthesis; D051940:B7-2 Antigen / Q000096:biosynthesis; D001886:Bordetella pertussis / Q000276:immunology; D039481:CD11b Antigen / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005260:Female; D016899:Interferon-beta / Q000276:immunology; D053583:Interleukin-1beta / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D017472:Receptors, Interleukin-1 / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014443:Tyrosine / Q000235:genetics
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D037361:Adenylate Cyclase Toxin; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D039481:CD11b Antigen; D016899:Interferon-beta; D053583:Interleukin-1beta; D015850:Interleukin-6; D053633:Receptor, Interferon alpha-beta; D017472:Receptors, Interleukin-1; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D014443:Tyrosine; C497965:Cd86 protein, mouse; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse