Enhanced effector and memory CTL responses generated by incorporation of receptor activator of NF-kappa B (RANK)/RANK ligand costimulatory molecules into dendritic cell immunogens expressing a human tumor-specific antigen.
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.
Wiethe
Carsten
C
Gesellschaft für Biotechnologische Forschung, Department of Molecular Biotechnology, Braunschweig, Germany.
Dittmar
Kurt
K
Doan
Tracy
T
Lindenmaier
Werner
W
Tindle
Robert
R
D000260:Adenoviruses, Human / Q000235:genetics / Q000276:immunology; D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000096:biosynthesis; D000951:Antigens, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D018122:B7-1 Antigen / Q000096:biosynthesis; D051940:B7-2 Antigen; D019013:CD40 Antigens / Q000096:biosynthesis; D023201:CD40 Ligand / Q000096:biosynthesis; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000235:genetics*; D004274:DNA, Recombinant / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D006023:Glycoproteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007156:Immunologic Memory / Q000235:genetics*; D008024:Ligands; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000502:physiology; D053244:Osteoprotegerin; D027383:Papillomaviridae / Q000235:genetics / Q000276:immunology; D050725:Papillomavirus E7 Proteins; D010957:Plasmids; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D014161:Transduction, Genetic; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
D015703:Antigens, CD; D000951:Antigens, Neoplasm; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019013:CD40 Antigens; C497964:CD86 protein, human; D002352:Carrier Proteins; D004274:DNA, Recombinant; D006023:Glycoproteins; D008024:Ligands; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D009856:Oncogene Proteins, Viral; D053244:Osteoprotegerin; D050725:Papillomavirus E7 Proteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; C059731:oncogene protein E7, Human papillomavirus type 16; D023201:CD40 Ligand