The long range goals of this project are to define the molecular specificity of cytolytic T lymphocytes (CTL) raised against esotropic murine leukemia viruses (MuLV); to determine whether it is possible to generate CTL that are specific for recombinant mink cell focus-inducing (MCF) MuLV and if so, to characterize these MCF MuLV directed CTL and define their molecular specificity; and to further determine the mechanism underlying the inability of the K-k class I major histocompatibility complex (MHC) gene of the MuLV-induced tumor AKR SL3 to show up-regulated expression in response to treatment with interferon gamma (IFN-gamma). The latter phenomenon of a differential resistance of MHC genes of a tumor to IFN-gamma up-regulation (because the D-k class I gene of AKR SL3 demonstrates normal responsiveness to IFN-gamma) may be indicative of a tumor escape mechanism from the H-2K restricted CTL responses that have been demonstrated to AKR/Gross MuLV-induced tumors. Thus, AKR SL3, which shows a low level of constitutive expression of the class I MHC K-k gene product that is required for CTL recognition and whose K-k gene additionally is IFN-gamma noninducible, may have become established via an immunoselection driven by anti-retroviral CTL. The studies proposed to define the molecular specificity of anti-retroviral CTL for MuLV-encoded determinants also have relevance to the understanding of leukemogenesis. Thus, in the AKR/Gross MuLV leukemogenesis model certain mouse strains such as AKR, which have a high incidence of spontaneous leukemia, express endogenous esotropic MuLV very early in life neonatally, if not before. This early expression of esotropic MuLV is necessary for subsequent leukemogenesis which begins at about six months of age just following the generation of recombinant retroviruses, including most notably the MCF MuLV that are generally considered to be the proximal transforming agent. Because it is widely thought that CTL are particularly effective against virus infected cells and tumor cells, it is important to understand to which MuLV CTL can be directed and their molecular specificity.
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