Protective CD8 T cell immunity triggered by CpG-protein conjugates competes with the efficacy of live vaccines.
In contrast to infectious (live) vaccines are those based on subunit Ag that are notoriously poor in eliciting protective CD8 T cell responses, presumably because subunit Ags become insufficiently cross-presented by dendritic cells (DCs) and because the latter need to be activated to acquire competence for cross-priming. In this study, we show that CpG-Ag complexes overcome these limitations. OVA covalently linked to CpG-DNA (CpG-OVA complex), once it is efficiently internalized by DCs via DNA receptor-mediated endocytosis, is translocated to lysosomal-associated membrane protein 1 (LAMP-1)-positive endosomal-lysosomal compartments recently shown to display competence for cross-presentation. In parallel, CpG-OVA complex loaded DCs become activated and acquire characteristics of professional APCs. In vivo, a single s.c. dose of CpG-OVA complex (10 mug of protein) induces primary and secondary clonal expansion/contraction of Ag-specific CD8 T cells similar in kinetics to live vaccines; examples including Listeria monocytogenes genetically engineered to produce OVA (LM-OVA) and two viral vector-based OVA vaccines analyzed. Interestingly, CpG-OVA complex induced almost equal percentages of Ag-specific memory CD8 T cells as did infection with LM-OVA. A single dose vaccination with CpG-OVA complex protected mice against lethal doses of LM-OVA. These data underscore that the synergy imparted by CpG-OVA complex-mediated combined triggering of innate and specific immunity might be key to initiate CD8 T cell-based immunoprotection by synthetic vaccines based on subunit Ag.
Heit
Antje
A
Institute of Medical Microbiology, Immunology and Hygiene, Technische Universität München, Germany.
Schmitz
Frank
F
O'Keeffe
Meredith
M
Staib
Caroline
C
Busch
Dirk H
DH
Wagner
Hermann
H
Huster
Katharina M
KM
D000818:Animals; D017951:Antigen Presentation; D000941:Antigens / Q000276:immunology; D001692:Biological Transport; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D011992:Endosomes; D007109:Immunity; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000276:immunology* / Q000493:pharmacokinetics; D010063:Ovum / Q000737:chemistry / Q000276:immunology*; D014612:Vaccines / Q000592:standards*
D000941:Antigens; C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; D014612:Vaccines