A triad of costimulatory molecules synergize to amplify T-cell activation

• Published in: Cancer research (Chicago, Ill.) Ill.), 1999-11, Vol.59 (22), p.5800-5807
• Main Authors: HODGE, J. W, SABZEVARI, H, YAFAL, A. G, GRITZ, L, LORENZ, M. G. O, SCHIOM, J
• Format: Article
• Language: English
• Subjects: AIDS/HIV; Animals; Antineoplastic agents; Apoptosis; B7-1 Antigen - genetics; B7-1 Antigen - immunology; B7-1 Antigen - metabolism; Biological and medical sciences; Carcinoembryonic Antigen - genetics; Carcinoembryonic Antigen - immunology; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD58 Antigens - genetics; CD58 Antigens - immunology; CD58 Antigens - metabolism; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cytokines - metabolism; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Expression Regulation, Viral; Genetic Vectors - genetics; Genetic Vectors - immunology; Humans; Immunobiology; Immunotherapy; Intercellular Adhesion Molecule-1 - genetics; Intercellular Adhesion Molecule-1 - immunology; Intercellular Adhesion Molecule-1 - metabolism; Lymphocyte Activation - physiology; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Modulation of the immune response (stimulation, suppression); Pharmacology. Drug treatments; Poxviridae - genetics; Recombination, Genetic; T-Lymphocytes - immunology; Transgenes; Tumor Cells, Cultured; Vaccinia - genetics
• ISSN: 0008-5472; 1538-7445

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.