Wild-Derived Inbred Mice Have a Novel Basis of Susceptibility to Polyomavirus-Induced Tumors

The murine polyomavirus can be a powerful oncogenic agent in its natural host, as evidenced by the rapid development of multiple solid tumors after inoculation of newborn animals (11, 19). Genetic backgrounds of both virus and host play important roles in determining the tumor response. By using a highly susceptible host, the effects of various determinants in the viral T (tumor) antigens involved in cell transformation (6, 14, 16, 38), as well as ones in the viral structural proteins with effects on receptor binding, cell penetration, and spread (2, 14, 36), have been investigated. The role of the host genetic background is complex and less well understood. Earlier studies of susceptible and resistant strains established an important role of the major histocompatibility complex (MHC) type and the ability to generate antitumor cellular immune responses (4, 17, 25, 27). Most resistant mouse strains show a radiation-sensitive form of resistance and become susceptible after radiation or neonatal thymectomy (1, 9, 26). A radiation-resistant or nonimmunological form of host resistance that acts by curtailing virus spread has also been described (9). In crosses between susceptible and resistant mice of the same MHC type (H-2k), susceptibility is inherited as a single dominant Mendelian trait (17, 30). This gene segregates with the endogenous mouse mammary tumor provirus Mtv-7 carried by the susceptible strain (28). C57BR/cdJ (BR) mice, used as the resistant parent, generate virus-specific cytotoxic T lymphocytes (CTLs) with a Vβ specificity (Vβ6) that would be deleted by the Mtv-7 superantigen (sag) present in all highly susceptible H-2k strains (28, 29). In the present study we first isolated and characterized a polyomavirus-specific CTL line from a virus-infected BR mouse and used it to investigate possible mechanisms of immune evasion by rare tumors that arise in this resistant strain. We describe a genetic and immunological basis of susceptibility to polyomavirus tumors manifested by two wild-derived inbred mouse strains. These highly susceptible wild inbreds are shown to be free of endogenous Mtvs and to express no sag(s) and yet, in crosses with BR mice, they transmit their susceptibility in a dominant fashion. Tumor cells derived from F1 animals are killed by CTLs from strain BR mice, demonstrating that these mice are able to process and present the appropriate viral epitope and that the tumor cells themselves are not intrinsically resistant to CTL killing. The wild-derived inbreds and their F1s have normal levels of CD8+ Vβ6+ T cells that are the expected precursors of polyomavirus-specific CTLs in this system. These results suggest a novel basis of tumor susceptibility involving a mechanism that interferes with the development of tumor immunity.