In vivo receptor-mediated delivery of a recombinant invasive bacterial toxoid to CD11c + CD8 alpha -CD11bhigh dendritic cells.

Abstract

The precise contribution of mouse dendritic cells (DC) CD8 alpha +CD11blow and CD8 alpha -CD11bhigh subsets to CTL priming is not fully defined. Here we show that CyaA, the adenylate cyclase toxin of Bordetella pertussis, an invasive bacterial toxin that binds cells through CD11b/CD18 can be exploited for the targeted delivery of an exogenous peptide to the CD8 alpha -CD11bhigh subset in vivo. Antigen (Ag) genetically inserted in the N-terminal domain of mutant CyaA devoid of catalytic activity, are targeted to CD8 alpha -CD11bhigh DC by the CD11b/CD18-dependent binding of CyaA to the cell surface. Ag is then presented by MHC class I molecules of CD8 alpha -CD11bhigh DC after a TAP-dependent, cytosolic processing. As a result, CTL are primed after a single injection, bypassing requirement for adjuvant, CD4+ T cell help and CD40 signaling. Beside the interest of the CyaA vector for vaccine development, these results show that Ag presentation focused on CD8 alpha -CD11bhigh DC in vivo is sufficient for eliciting a vigorous CTL response and that CD11b/CD18 could be a suitable surface molecule for targeting Ag to DC.