Antigen targeting to CD11b allows efficient presentation of CD4+ and CD8+ T cell epitopes and in vivo Th1-polarized T cell priming.
Bordetella pertussis adenylate cyclase (CyaA) is an invasive bacterial toxin that delivers its N-terminal catalytic domain into the cytosol of eukaryotic cells bearing the alpha(M)beta(2) integrin (CD11b/CD18), such as myeloid dendritic cells. This allows use of engineered CyaA for targeted delivery of CD8(+) T cell epitopes into the MHC class I pathway of APC and induction of robust and protective cytotoxic responses. In this study, we demonstrate that CyaA can efficiently codeliver both a CD8(+) T cell epitope (OVA(257-264)) and a CD4(+) T cell epitope (MalE(100-114)) into, respectively, the conventional cytosolic or endocytic routes of processing of murine bone marrow-derived dendritic cells. Upon CyaA delivery, a strong potentiation of the MalE(100-114) CD4(+) T cell epitope presentation is observed as compared with the MalE protein, which depends on CyaA interaction with its CD11b receptor and its subsequent clathrin-mediated endocytosis. In vivo, CyaA induces strong and specific Th1 CD4(+) and CD8(+) T cell responses against, respectively, the MalE(100-114) and OVA(257-264) epitopes. These results underscore the potency of CyaA for design of new vaccines.
Schlecht
Géraldine
G
Unité de Biologie des Régulations Immunitaires, Institut National de la Santé et de la Recherche Médicale E 352, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris cedex 15, Paris, France.
Loucka
Jirina
J
Najar
Hossain
H
Sebo
Peter
P
Leclerc
Claude
C
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D037361:Adenylate Cyclase Toxin / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D001854:Bone Marrow Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D022163:Clathrin-Coated Vesicles / Q000502:physiology; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D011992:Endosomes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D005260:Female; D017930:Genes, Reporter; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006825:Hybridomas; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010047:Ovalbumin / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010447:Peptide Hydrolases / Q000502:physiology; D033902:Periplasmic Binding Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D018417:Th1 Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D014617:Vacuoles / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; C503300:Abcb9 protein, mouse; D000199:Actins; D037361:Adenylate Cyclase Toxin; D039481:CD11b Antigen; D018984:Epitopes, T-Lymphocyte; D029968:Escherichia coli Proteins; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; C461619:MalE protein, E coli; C110366:OVA-8; D010446:Peptide Fragments; D033902:Periplasmic Binding Proteins; D014614:Vaccines, Synthetic; D010047:Ovalbumin; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex