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.

• MeSH
• adaptorové proteiny vezikulární transportní imunologie   MeSH
• adenylátcyklasový toxin imunologie   MeSH
• antigeny CD11b imunologie   MeSH
• antigeny CD80 biosyntéza   MeSH
• antigeny CD86 biosyntéza   MeSH
• Bordetella pertussis imunologie   MeSH
• buněčná diferenciace imunologie   MeSH
• cytotoxické T-lymfocyty imunologie   MeSH
• dendritické buňky cytologie   imunologie   MeSH
• interferon beta imunologie   MeSH
• interleukin-1beta biosyntéza   MeSH
• interleukin-6 biosyntéza   MeSH
• kultivované buňky MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• receptor interferonu alfa-beta genetika   MeSH
• receptory interleukinu-1 imunologie   MeSH
• signální transdukce imunologie   MeSH
• TNF-alfa biosyntéza   MeSH
• toll-like receptor 4 imunologie   MeSH
• tyrosin genetika   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH