In vivo receptor-mediated delivery of a recombinant invasive bacterial toxoid to CD11c + CD8 alpha -CD11bhigh dendritic cells.
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.
Guermonprez
Pierre
P
Unit of Biology of Immune Regulations, Institut Pasteur, Paris, France.
Fayolle
Catherine
C
Rojas
Marie-Jésus
MJ
Rescigno
Maria
M
Ladant
Daniel
D
Leclerc
Claude
C
D037361:Adenylate Cyclase Toxin / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D017951:Antigen Presentation; D039481:CD11b Antigen / Q000032:analysis; D039521:CD11c Antigen / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D002460:Cell Line; D003600:Cytosol / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism*; D005260:Female; D007114:Immunization; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology; D011994:Recombinant Proteins / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014121:Toxoids / Q000378:metabolism*
D037361:Adenylate Cyclase Toxin; D039481:CD11b Antigen; D039521:CD11c Antigen; D016827:CD8 Antigens; D011994:Recombinant Proteins; D014121:Toxoids; D010047:Ovalbumin