CD137 costimulation of CD8⁺ T cells confers resistance to suppression by virus-induced regulatory T cells

Chronic viral infections cause high levels of morbidity and mortality worldwide, making the development of effective therapies a high priority for improving human health. We have used mice infected with Friend virus as a model to study immunotherapeutic approaches to the cure of chronic retroviral infections. In chronic Friend virus infections CD4⁺ T regulatory (Treg) cells suppress CD8⁺ T cell effector functions critical for virus clearance. In this study, we demonstrate that immunotherapy with a combination of agonistic anti-CD137 Ab and virus-specific, TCR-transgenic CD8⁺ T cells produced greater than 99% reductions of virus levels within 2 wk. In vitro studies indicated that the CD137-specific Ab rendered the CD8⁺ T cells resistant to Treg cell-mediated suppression with no direct effect on the suppressive function of the Treg cells. By 2 weeks after transfer, the adoptively transferred CD8⁺ T cells were lost, likely due to activation-induced cell death. The highly focused immunological pressure placed on the virus by the single specificity CD8⁺ T cells led to the appearance of escape variants, indicating that broader epitope specificity will be required for long-term virus control. However, the results demonstrate a potent strategy to potentiate the function of CD8⁺ T cells in the context of immunosuppressive Treg cells.