Cytotoxic T lymphocytes (CTL or killer T lymphocytes) play a critical role in the rejection of virally-induced tumors and the elimination of viral infections by the host. Yet the way in which CTL recognize their targets is unknown. Indeed, even which viral or tumor viral protein (if any) is recognized by CTL is not clear. Part of the difficulty involved in the study of CTL interaction with virus-infected cells or tumors lies in the number of viral proteins made by the virus, our inability to modulate the expression of these proteins, and the cytopathic effects induced by these viruses. These problems have been overcome by a system we have developed that utilizes cloned viral genes to allow expression of single viral proteins on the surface of uninfected (and nontumor) mouse cells. Preliminary data shows that such cells are recognized and killed by virus-specific or tumor-specific CTL, as if they were true infected cells or tumor cells. It is possible to alter the levels of antigen expression in these cells. The system also facilitates the use of in vitro, site-directed mutagenesis to alter the viral gene products. This technique provides a new and powerful way of studying cell-mediated host defenses against viral infections and tumors. This model system is being used to probe CTL-target cell interactions and will establish: (1) which virus or tumor virus proteins are being recognized by CTL; (2) the number of antigen molecules per cell required for CTL recognition; (3) the presence or absence of physical association between the viral antigens and the cellular H-2 antigens and the hierarchy of such associations; and (4) which structural areas on the viral antigen are being recognized by CTL and whether they differ from the areas recognized by antibodies. Establishing the answers to such basic questions is vital if we are to understand the way in which CTL carry out their immune surveillance against infections and tumors, why some tumors and not others are destroyed, and the possible ways in which CTL-mediated destruction of infected cells or tumors could be augmented in the patient. Our ability to selectively mutagenize the viral genes and present them more physiologically to CTL precursors (i.e., on a cell membrane and in the context of H-2 antigens) could be used to possibly enhance the host response to malignancy and lead to the development of a T-cell-specific vaccine. (AG)
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