A triad of costimulatory molecules synergize to amplify T-cell activation in both vector-based and vector-infected dendritic cell vaccines.
The activation of a T cell has been shown to require two signals via molecules present on professional antigen presenting cells: signal 1, via a peptide/MHC complex, and signal 2, via a costimulatory molecule. Here, the role of three costimulatory molecules in the activation of T cells was examined. Poxvirus (vaccinia and avipox) vectors were employed because of their ability to efficiently express multiple genes. Murine cells provided with signal 1 and infected with either recombinant vaccinia or avipox vectors containing a TRIad of COstimulatory Molecules (B7-1/ICAM-1/LFA-3, designated TRICOM) induced the activation of T cells to a far greater extent than cells infected with vectors expressing any one or two costimulatory molecules. Despite this T-cell "hyperstimulation" using TRICOM vectors, no evidence of apoptosis above that seen using the B7-1 vector was observed. Results employing the TRICOM vectors were most dramatic under conditions of either low levels of first signal or low stimulator cell to T-cell ratios. Experiments employing a four-gene construct also showed that TRICOM recombinants could enhance antigen-specific T-cell responses in vivo. These studies thus demonstrate the ability of vectors to introduce three costimulatory molecules into cells, thereby activating both CD4+ and CD8+ T-cell populations to levels greater than those achieved with the use of only one or two costimulatory molecules. This new threshold of T-cell activation has broad implications in vaccine design and development. Dendritic cells infected with TRICOM vectors were found to greatly enhance naïve T-cell activation, and peptide-specific T-cell stimulation. In vivo, peptide-pulsed DCs infected with TRICOM vectors induced cytotoxic T lymphocyte activity markedly and significantly greater than peptide-pulsed DCs.
Schlom
J
J
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. js141c@nih.gov
Sabzevari
H
H
Grosenbach
D W
DW
Hodge
J W
JW
D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects; D018122:B7-1 Antigen / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018968:CD58 Antigens / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D004357:Drug Synergism; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D018799:Intercellular Adhesion Molecule-1 / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D011212:Poxviridae / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*
D018122:B7-1 Antigen; D018968:CD58 Antigens; D016207:Cytokines; D018799:Intercellular Adhesion Molecule-1