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CD137 Costimulation of CD8⁺ T Cells Confers Resistance to Suppression by Virus-Induced Regulatory T Cells¹

Shelly J. Robertson^*, Ronald J. Messer^*, Aaron B. Carmody^*, Robert S. Mittler, Christopher Burlak^* and Kim J. Hasenkrug^2,*

^* Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840; and Department of Surgery and Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30329

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by the National Institute of Allergy and Infectious Diseases Division of Intramural Research, National Institutes of Health.

² Address correspondence and reprint requests to Dr. Kim J. Hasenkrug, Rocky Mountain Laboratories, National Institutes of Health, 903 South 4th Street, Hamilton, MT 59840. E-mail address: khasenkrug{at}nih.gov

³ Abbreviations used in this paper: FV, Friend retrovirus complex; F-MuLV, Friend virus; Treg, regulatory T; Tg, transgenic; PD-1, programmed cell death 1.