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 molecu les present on professional antigen-presenting cells: signal 1, via a pepti de/MHC complex; and signal, via a costimulatory molecule. Here, the role of three costimulatory molecules in the activation of T cells was examined. P oxvirus (vaccinia and avipox) vectors ere 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 T RIad of COstimulatory Molecules (B7-1/ICAM-1/LFA-3, designated TRICOM) indu ced the activation of T cells to a far greater extent than cells infected w ith any one or two costimulatory molecules. Despite this T-cell "hyperstimu lation" using TRICOM vectors, no evidence of apoptosis above that seen usin g 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 stimu lator cell:l-cell ratios. Experiments using a four-gene construct also show ed that TRICOm recombinants can enhance antigen-specific T-cell responses i n vivo. These studies thus demonstrate for the first time the ability of ve ctors to introduce three costimulatory molecules into cells, thereby activa ting 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 an d development.