Susceptibility to tumors induced by polyoma virus is conferred by an endogenous mouse mammary tumor virus superantigen.

Abstract

SumrrlaryA dominant gene carried in certain inbred mouse strains confers susceptibility to tumors induced by polyoma virus. This gene, designated Pyv s, was defined in crosses between the highly susceptible C3H/BiDa strain and the highly resistant but H-2k-identical C57BR/cdJ strain. The resistance of C57BR/cdJ mice is overcome by irradiation, indicating an immunological basis. In F1 x C57BR/cdJ backcross mice, tumor susceptibility cosegregates with Mtv-7, a mouse mammary tumor provirus carried by the C3H/BiDa strain. This suggests that Pyv s might encode the Mtv-7 superantigen (SAG) and abrogate polyoma tumor immunosurveillance through elimination of T cells bearing specific VB domains. DNA typing of 110 backcross mice showed no evidence of recombination between Pyv s and Mtv-7. Strongly biased usage of VB6 by polyoma virus-specific CD8 § cytotoxic T lymphocytes in C57BR/cdJ mice implicates T cells bearing this Mtv-7 SAG-reactive VB domain as critical anti-polyoma tumor effector cells in vivo. These results indicate identity between Pyv s and Mtv-7 sag, and demonstrate a novel mechanism of inherited susceptibility to virus-induced tumors based on effects of an endogenous superantigen on the host's T cell repertoire.

Polyoma Virus-Like Particles Elicit Polarized Cytokine Responses in APCs from Tumor-Susceptible and -Resistant Mice

“…Innate immune responses in mice to the oncogenic polyoma virus differ among inbred strains and are linked to dramatically different outcomes. BR mice respond with a type 1 cytokine response leading to effective T cell immunity against the viral T Ags and to protection against tumor development (5,6,14). A type 2 response develops in infected PE and (PE ϫ BR) F 1 mice, which fail to mount a sustained T cell response and develop multiple tumors (14).…”

“…The T Ags of Py and the closely related primate polyoma virus SV40 comprise the classically defined "tumorspecific transplantation Ags" of these viruses. Rejection is based primarily on cytolytic CD8 ϩ T cells specific for MHC-restricted T Agderived peptides (5)(6)(7)(8)(9)(10). Interestingly, in certain crosses between tumor-susceptible and tumor-resistant mice of the same H2 haplotype, susceptibility is found to be dominant (5,11,12).…”

“…Rejection is based primarily on cytolytic CD8 ϩ T cells specific for MHC-restricted T Agderived peptides (5)(6)(7)(8)(9)(10). Interestingly, in certain crosses between tumor-susceptible and tumor-resistant mice of the same H2 haplotype, susceptibility is found to be dominant (5,11,12). Mechanisms that prevent the development or maintenance of tumor immunity must therefore be operating in these susceptible hosts.…”

“…Among the most highly susceptible hosts are H2 k strains that carry an endogenous mouse mammary tumor virus (MMTV). Expression of the superantigen Mtv-7 Sag in these strains during late prenatal and early postnatal life leads to deletion of V␤6 ϩ CTL precursors needed for rejection of Py tumors in H2 k mice (5). C57BR/cdj (BR) mice, which are H2 k but lack Mtv-7, mount V␤6 ϩ CD8 ϩ T cell responses and develop no tumors (12).…”

A Large Number of T Lymphocytes Recognize Moloney-Murine Leukemia Virus-Induced Antigens, but a Few Mediate Long-Lasting Tumor Immunosurveillance

“…TCR flexibility seems to occur also in the CD8 ϩ T cell response to Moloney-murine leukemia virus (M-MuLV) 3 induced Ags; while C57BL/6 (B6) mice preferentially use TCRV␤5 expressing T cells to reject M-MuLV-infected tumor cells (17), congenic B6.V␤ a mice, in which the dominant V␤5 chain is not expressed, use alternative V␤ chains to recognize the same immunodominant epitope (18). However, previous observations speak against a class I-restricted TCR repertoire flexibility because the elimination of T cells bearing the specific V␤ region for virus-or chemically induced tumor Ag(s), through endogenous superantigen expression, abrogates tumor immunosurveillance (19,20).…”