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Mechanisms of thymic lymphomagenesis by the retrovirus SL3-3
E F Hays1, G Bristol, S McDougall
1Laboratory of Biomedical and Environmental Sciences, Los Angeles, California 90024-1786.
Abstract:
These studies report changes occurring in the thymus of AKR and NFS/N mice after infection with the lymphomagenic retrovirus SL3-3. In virus-infected AKR fetal thymus, the programmed cell death caused by treatment with antibody to CD3 was remarkably diminished. A method of establishing thymic stromal cultures from mice of 1 to 3 wk of age is described. Using this method, it was found that SL3-3 virus infection by neonatal inoculation allowed establishment of thymic stromal cultures from organs removed from AKR mice of 30 to 50 days of age and from lymphomas, whereas thymic stromal cultures could not be established from control mice after 30 days of age. Using NFS/N mice which have no endogenous virus, it was shown that infection of thymic stroma precedes infection of thymocytes and that thymocytes are permissive for infection with SL3-3 virus but not for the nononcogenic retrovirus, Akv, yet Akv virus replicates efficiently in thymic stroma. SL3-3 virus integrates randomly in each lymphoma induced by this virus. The lymphomas are clonal or oligoclonal. Pim-1 and c-myc genes commonly rearranged in other virus-induced thymic lymphoma showed rearrangement in only a few lymphomas. A theory is proposed, based on the work presented here and in recent studies, which states that SL3-3 virus infection of thymic stroma allows infection of thymocyte progenitors entering from the bone marrow. These cells are then altered so that their maturation is delayed and their intrathymic survival is prolonged. This permits virus integration and reintegration that results in the genetic changes which transform the cell.
Insights
SL3-3 retrovirus infection alters the thymus, diminishing programmed cell death and enabling stromal cell culture establishment. This retrovirus infection of thymic stroma precedes thymocyte infection, leading to altered cell maturation and prolonged survival, ultimately causing lymphoma.
Area of Science:
- Immunology
- Virology
- Oncology
Background:
- The thymus is crucial for T-cell development.
- Lymphomagenic retroviruses can induce thymic lymphomas.
- Understanding retroviral pathogenesis in the thymus is vital.
Purpose of the Study:
- To investigate the effects of SL3-3 retrovirus infection on the thymus.
- To characterize the changes in thymic stromal cells and thymocytes following infection.
- To propose a mechanism for SL3-3-induced lymphomagenesis.
Main Methods:
- Infection of AKR and NFS/N mice with SL3-3 retrovirus.
- Establishment and culture of thymic stromal cells.
- Analysis of programmed cell death and viral integration.
- Comparison of SL3-3 and Akv retrovirus infections.
Main Results:
- SL3-3 infection diminished programmed cell death in fetal thymus.
- Thymic stromal cultures could be established from infected mice, unlike controls.
- Thymic stroma infection precedes thymocyte infection.
- SL3-3 infected thymocytes, but not Akv, while Akv replicated in stroma.
- Lymphomas were clonal/oligoclonal with random SL3-3 integration.
Conclusions:
- SL3-3 retrovirus infects thymic stroma, facilitating subsequent thymocyte progenitor infection.
- Altered maturation and prolonged survival of infected cells promote viral integration and transformation.
- This mechanism explains SL3-3-induced thymic lymphoma development.