Mechanisms of the H-2 effect on viral leukemogenesis.

Evidence has been gathered which supports the notion that two distinct but interacting mechanisms, controlled by loci mapping within the H-2 complex, influence Friend murine leukemia virus (FV) disease. One mechanism, controlled by a gene mapping in or close to H-2D, influences the capacity of the H-2D gene product to form molecular complexes with FV molecules in the plasma membrane of infected cells. Formation of a complex appears to provide a target antigen for syngeneic cytotoxic T-lymphocytes, to cause co-capping of FV and H-2D antigens, to permit the selective inclusion of H-2Db molecules into progeny Friend virions, to influence the long-term maintenance of virus production in vitro and, in conjunction with the second mechanism, to stimulate the generation of cytotoxic T-lymphocytes. This second mechanism is controlled by a gene in the H-2K or H-2I region, and, in the presence of an H-2/FV molecular complex immunogen, influences the generation of H-2 restricted cytotxic T-lymphocytes and the rate of rejection of syngeneic FV-induced tumor cells.

Antigenic properties of cultured tumor cell lines derived from spleens of Friend virus-infected BALB/c and BALB/c-H-2b mice.

BALB/c-H-2b (BALB.B) mice are less susceptible to the Friend virus (FV) disease syndrome than congenic BALB/c (H-2d) mice, and spleen cells from FV-infected BALB.B mice are markedly less tumorigenic on transplantation to syngeneic hosts than those from FV-infected BALB/c mice. For these reasons we investigated the expression of FV-associated cell surface antigens on cultured, FV-trnasformed cell lines of BALB.B and BALB/c origin. Both cell lines induced transplantation immunity in syngeneic hosts toward further implantations of the same tumor, BALB.B cells being significantly more potent in this respect than BALB/c cells. BALB.B tumor cells, which produce complete, infectious FV, expressed both the cell surface antigen, FMR (corresponding to the cytotoxic antibodies in anti-FV antisera), and virus envelope antigen (VEA, corresponding to the virus-neutralizing antibodies in the anti-FV antisera). BALB/c tumor cells, on the other hand, which are FV-nonproducers, expressed no FMR antigen, but did express VEA on their surfaces for at least 100 passages in culture. These cells could induce FV-neutralizing but not cytotoxic anti-FMR antibodies when used to immunize syngeneic hosts. The absence of FMR antigen may be the basis for the reduced capacity of BALB/c tumor cells, by comparison with BALB.B tumor cells, to induce transplantation immunity. After about the 125th serial transfer in culture, BALB/c tumor cells spontaneously ceased to express VEA and simultaneously became very weak inducers of transplantation immunity in BALB/c hosts. This loss of VEA did not stem from the loss of either the spleen focus-forming virus or the helper virus genomes from these cells, since both viruses could still be recovered from the cell line.

Properties of cell lines derived from tumors induced by Friend virus in BALB/c and BALB/c-H-2b mice.

Cell lines have been established in culture from Friend virus-induced tumors of BALB/c (H-2d) and congenic BALB/c-H-2b (BALB.B) origin. Spleens from virus-infected hosts in the terminal stages of erythroleukemic disease provided tissues for the establishment of subcutaneously transplantable tumors of both strains. Subsequently cells of these tumors were introduced into culture and passed serially. Complete, infectious Friend virus (FV) has been routinely recovered from culture supernates of BALB.B tumor cells (HFL/b) throughout its 2-yr passage history. However, after only a few transfer generations in culture BALB/c tumor cells (HFL/d) became nonproducers of virus detectable in either the spleen focus assay in vivo or the XC assay in vitro. Nonproducer HFL/d cells possessed the complete genomes of the components of the FV complex, since FV could be recovered from them either by cocultivation with helper virus-infected syngeneic embryo fibroblasts or by serial passage in the ascitic form in normal, syngeneic adult hosts.