Abstract
The outcome of dendritic cell (DC) presentation of Ag to T cells via the TCR/MHC synapse is determined by second signaling through CD80/86 and, importantly, by ligation of costimulatory ligands and receptors located at the DC and T cell surfaces. Downstream signaling triggered by costimulatory molecule ligation results in reciprocal DC and T cell activation and survival, which predisposes to enhanced T cell-mediated immune responses. In this study, we used adenoviral vectors to express a model tumor Ag (the E7 oncoprotein of human papillomavirus 16) with or without coexpression of receptor activator of NF-kappaB (RANK)/RANK ligand (RANKL) or CD40/CD40L costimulatory molecules, and used these transgenic DCs to immunize mice for the generation of E7-directed CD8(+) T cell responses. We show that coexpression of RANK/RANKL, but not CD40/CD40L, in E7-expressing DCs augmented E7-specific IFN-gamma-secreting effector and memory T cells and E7-specific CTLs. These responses were also augmented by coexpression of T cell costimulatory molecules (RANKL and CD40L) or DC costimulatory molecules (RANK and CD40) in the E7-expressing DC immunogens. Augmentation of CTL responses correlated with up-regulation of CD80 and CD86 expression in DCs transduced with costimulatory molecules, suggesting a mechanism for enhanced T cell activation/survival. These results have generic implications for improved tumor Ag-expressing DC vaccines, and specific implications for a DC-based vaccine approach for human papillomavirus 16-associated cervical carcinoma.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenoviruses, Human / genetics
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Adenoviruses, Human / immunology
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Amino Acid Sequence
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Antigens, CD / biosynthesis
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Antigens, Neoplasm / biosynthesis*
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Antigens, Neoplasm / genetics
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B7-1 Antigen / biosynthesis
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B7-2 Antigen
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CD40 Antigens / biosynthesis
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CD40 Ligand / biosynthesis
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Carrier Proteins / biosynthesis
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Carrier Proteins / genetics*
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Carrier Proteins / metabolism
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Carrier Proteins / physiology
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Cell Line
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Cell Line, Tumor
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Cytotoxicity, Immunologic / genetics*
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DNA, Recombinant / genetics
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism
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Dendritic Cells / virology
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Glycoproteins / biosynthesis
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Glycoproteins / genetics*
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Glycoproteins / metabolism
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Glycoproteins / physiology
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Humans
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Immunologic Memory / genetics*
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Ligands
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Membrane Glycoproteins / biosynthesis
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Membrane Glycoproteins / genetics*
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Membrane Glycoproteins / metabolism
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Membrane Glycoproteins / physiology
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Molecular Sequence Data
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NF-kappa B / metabolism
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Oncogene Proteins, Viral / genetics
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Oncogene Proteins, Viral / physiology
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Osteoprotegerin
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Papillomaviridae / genetics
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Papillomaviridae / immunology
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Papillomavirus E7 Proteins
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Plasmids
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RANK Ligand
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Receptor Activator of Nuclear Factor-kappa B
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Receptors, Cytoplasmic and Nuclear / biosynthesis
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Receptors, Cytoplasmic and Nuclear / genetics*
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Receptors, Cytoplasmic and Nuclear / metabolism
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Receptors, Cytoplasmic and Nuclear / physiology
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Receptors, Tumor Necrosis Factor
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Signal Transduction / genetics
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Signal Transduction / immunology
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T-Lymphocytes, Cytotoxic / immunology*
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T-Lymphocytes, Cytotoxic / metabolism
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T-Lymphocytes, Cytotoxic / virology
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Transduction, Genetic
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Up-Regulation / genetics
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Up-Regulation / immunology*
Substances
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Antigens, CD
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Antigens, Neoplasm
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B7-1 Antigen
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B7-2 Antigen
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CD40 Antigens
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CD86 protein, human
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Carrier Proteins
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DNA, Recombinant
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Glycoproteins
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Ligands
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Membrane Glycoproteins
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NF-kappa B
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Oncogene Proteins, Viral
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Osteoprotegerin
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Papillomavirus E7 Proteins
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RANK Ligand
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Receptor Activator of Nuclear Factor-kappa B
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Receptors, Cytoplasmic and Nuclear
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Receptors, Tumor Necrosis Factor
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TNFRSF11A protein, human
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TNFRSF11B protein, human
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TNFSF11 protein, human
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oncogene protein E7, Human papillomavirus type 16
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CD40 Ligand