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.
Robertson
Shelly J
SJ
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA.
Messer
Ronald J
RJ
Carmody
Aaron B
AB
Mittler
Robert S
RS
Burlak
Christopher
C
Hasenkrug
Kim J
KJ
D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005622:Friend murine leukemia virus / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012192:Retroviridae Infections / Q000276:immunology* / Q000628:therapy / Q000821:virology; D013154:Spleen / Q000821:virology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology* / Q000378:metabolism; D014412:Tumor Virus Infections / Q000276:immunology / Q000628:therapy / Q000821:virology
D000906:Antibodies; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9