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

Shelly J. Robertson, Ronald J. Messer, Aaron B. Carmody, Robert S. Mittler, Christopher Burlak, Kim J. Hasenkrug

Research output: Contribution to journalArticlepeer-review

39 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)5267-5274
Number of pages8
JournalJournal of Immunology
Issue number8
StatePublished - Apr 15 2008


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