A triad of costimulatory molecules synergize to amplify T-cell activation.
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 used 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 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 using the TRICOM vectors were most dramatic under conditions of either low levels of first signal or low stimulator cell:T-cell ratios. Experiments using a four-gene construct also showed that TRICOM recombinants can enhance antigen-specific T-cell responses in vivo. These studies thus demonstrate for the first time 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.
Hodge
J W
JW
Laboratory of Tumor Immunology and Biology, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Sabzevari
H
H
Yafal
A G
AG
Gritz
L
L
Lorenz
M G
MG
Schlom
J
J
D000818:Animals; D017209:Apoptosis; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018968:CD58 Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D005260:Female; D015967:Gene Expression Regulation, Viral; D005822:Genetic Vectors / Q000235:genetics / Q000276:immunology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011212:Poxviridae / Q000235:genetics; D011995:Recombination, Genetic; D013601:T-Lymphocytes / Q000276:immunology*; D019076:Transgenes; D014407:Tumor Cells, Cultured; D014615:Vaccinia / Q000235:genetics
D018122:B7-1 Antigen; D018968:CD58 Antigens; D002272:Carcinoembryonic Antigen; D016207:Cytokines; D018799:Intercellular Adhesion Molecule-1