Wild-derived inbred mice have a novel basis of susceptibility to polyomavirus-induced tumors

Abstract

Polyomavirus induces a broad array of tumors when introduced into newborn mice of certain standard inbred strains, notably those bearing the H-2(k) haplotype. Susceptibility in these mice is conferred by an endogenous mouse mammary tumor virus superantigen (Mtv-7 sag) that acts to delete T cells required for polyomavirus-induced tumor immunosurveillance. In the present study we show that mice of two wild-derived inbred strains, PERA/Ei (PE) and CZECH II/Ei (CZ), are highly susceptible to polyomavirus but carry no detectable Mtv sag-related sequences and show no evidence of Vbeta deletion. C57BR/cdJ (BR) mice, which are H-2(k) but lack the endogenous Mtv-7, are highly resistant based on an effective anti-polyomavirus tumor immune response. When crossed with BR, both PE and CZ mice transmit their susceptibility in a dominant fashion, indicating a mechanism(s) that overrides the immune response of BR. Susceptibility in PE and CZ mice is not based on interference with antigen processing or presentation since cytotoxic T cells from BR can efficiently kill F(1)-derived tumor cells in vitro. The expected precursors of polyomavirus-specific cytotoxic T cells are present in both the wild inbred animals and their F(1) progeny. These findings indicate a novel basis of susceptibility that operates independently of endogenous superantigen and prevents the development of tumor immunity.

FIG. 1

Test for polyomavirus DNA sequences in tumors from BR mice. A-6215 is an immunogenic tumor from an irradiated virus-infected mouse, A-6241 is a nonimmunogenic tumor from an unirradiated virus-infected mouse, and A-6689 is another nonimmunogenic tumor from an unirradiated virus-infected mouse. On the left are molecular size markers. The arrow on the right indicates the position of the expected 542-bp DNA product. PCR was carried out for polyomavirus middle T-coding sequences. A PCR control is shown at the bottom of the figure.

FIG. 2

Tests for Mtv-7 Sag and other MMTV sag sequences in genomic DNAs of various mouse strains. (Left) PCR product for Mtv-7 sag-specific sequences. Lanes (left to right): C3H/BiDa, BR, PE, CZ, and markers. The arrow indicates the position of the predicted 319-bp product. (Right) PCR product for common MMTV sag sequences. Lanes (left to right): markers, C3H/BiDa, BR, PE, and CZ. The arrow indicates the position of the predicted 1,018-bp product. A PCR control is shown at the bottom of the figure. PCR was carried out as described in Materials and Methods.

FIG. 3

FACS analysis of H-2 haplotype in wild-derived mouse strains. Splenocytes from BR, PE, and CZ mice were stained with the FITC-labeled anti-MHC class I (H-2^k) MAb. A monoclonal mouse IgG1 was used as a negative control. Spleen cells of BR mice served as a positive control. The analysis was performed by using a flow cytometer after gating on the viable cell population as determined by forward- and side-scatter analysis. Positive staining and fluorescence intensity (log scale) for 10,000 events are shown. The histograms represent one of three experiments. Similar results were obtained by using anti-class II (H-2^k) MAb. The levels of surface positive cells were <1% with anti-H-2^b class I MAb compared to >90% with anti-H-2^k MAb (BR and PE mice).