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Loss of endogenous mouse mammary tumor virus superantigen increases tumor resistance
V Schirrmacher1, U Beutner, M Bucur
1Division of Cellular Immunology, German Cancer Research Center, Heidelberg. v.schirrmacher@dkfz-heidelberg.de
Abstract:
From a cross between a tumor-susceptible mouse strain (DBA/2; D) and a tumor-resistant MHC-identical strain (B10.D2; D2) new recombinant inbred mouse strains were established over many generations of inbreeding and tumor resistance selection. Since resistance to the highly metastatic DBA/2 lymphoma variant ESb had an immunologic basis, and the two parental strains differed in endogenous viral superantigens (vSAGs), DNA of three D2 x D recombinant inbred mouse lines was typed for endogenous mouse mammary tumor viruses using mouse mammary tumor virus long terminal repeat- and env gene-specific probes. The resistant D2 x D mice were very similar to the susceptible parental strain D in their Mtv Southern blots, except for the lack of a single band corresponding to Mtv-7, the provirus coding for the strong DBA/2 superantigen Mls-1a. A backcross analysis revealed that Mtv-7-negative F2 mice were significantly more resistant than Mtv-7-positive F2 mice. When Mtv-7 was reintroduced into the resistant lines by crossing them with either CBA/J or BALB/D2.Mls-1a, the mice became again more tumor susceptible. Finally, we demonstrate the ability to transfer immunoresistance and graft-vs-leukemia reactivity from tumor-resistant to tumor-susceptible mice.
Insights
Tumor resistance in mice is linked to the absence of Mtv-7, a specific viral superantigen. Removing Mtv-7 enhances resistance, while its presence increases tumor susceptibility.
Area of Science:
- Immunogenetics
- Virology
- Oncology
Background:
- Recombinant inbred mouse strains were developed from tumor-susceptible (DBA/2) and tumor-resistant (B10.D2) parents.
- Tumor resistance has an immunologic basis and is influenced by endogenous viral superantigens (vSAGs).
Purpose of the Study:
- To investigate the genetic basis of tumor resistance in new recombinant inbred mouse strains.
- To identify specific endogenous mouse mammary tumor viruses (Mtvs) associated with tumor resistance.
Main Methods:
- DNA typing of recombinant inbred mouse lines for endogenous mouse mammary tumor viruses using Mtv long terminal repeat and env gene probes.
- Southern blot analysis to detect Mtv proviruses.
- Backcross analysis to assess the association between Mtv-7 and tumor resistance.
Main Results:
- Resistant D2 x D mice lacked Mtv-7, a provirus encoding the Mls-1a superantigen.
- Mtv-7-negative F2 mice showed significantly higher resistance to tumors compared to Mtv-7-positive F2 mice.
- Reintroduction of Mtv-7 into resistant lines increased tumor susceptibility.
Conclusions:
- The absence of Mtv-7 is strongly correlated with tumor resistance.
- Mtv-7 plays a crucial role in modulating tumor susceptibility.
- Immunoresistance and graft-vs-leukemia reactivity can be transferred between mice.