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Journal of Virology, June 2005, p. 7852-7859, Vol. 79, No. 12
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.12.7852-7859.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Regulatory T Cells Suppress In Vitro Proliferation of Virus-Specific CD8⁺ T Cells during Persistent Hepatitis C Virus Infection

Simon M. Rushbrook,^1, Scott M. Ward,^2, Esther Unitt,¹ Sarah L. Vowler,³ Michaela Lucas,^2, Paul Klenerman,^2* and Graeme J. M. Alexander¹

Department of Medicine, School of Clinical Medicine, University of Cambridge, Hills Road, Cambridge CB2 2SP, United Kingdom,¹ Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford, South Parks Road, Oxford OX1 3SY, United Kingdom,² Centre for Applied Medical Statistics, Department of Public Health and Primary Care, University of Cambridge, Hills Road, Cambridge CB2 2SP, United Kingdom³

Received 11 October 2004/ Accepted 7 February 2005

The basis of chronic infection following exposure to hepatitis C virus (HCV) infection is unexplained. One factor may be the low frequency and immature phenotype of virus-specific CD8⁺ T cells. The role of CD4⁺CD25⁺ T regulatory (T_reg) cells in priming and expanding virus-specific CD8⁺ T cells was investigated. Twenty HLA-A2-positive patients with persistent HCV infection and 46 healthy controls were studied. Virus-specific CD8⁺ T-cell proliferation and gamma interferon (IFN-) frequency were analyzed with/without depletion of T_reg cells, using peptides derived from HCV, Epstein-Barr virus (EBV), and cytomegalovirus (CMV). CD4⁺CD25⁺ T_reg cells inhibited anti-CD3/CD28 CD8⁺ T-cell proliferation and perforin expression. Depletion of CD4⁺CD25⁺ T_reg cells from chronic HCV patients in vitro increased HCV and EBV peptide-driven expansion (P = 0.0005 and P = 0.002, respectively) and also the number of HCV- and EBV-specific IFN--expressing CD8⁺ T cells. Although stimulated CD8⁺ T cells expressed receptors for transforming growth factor beta and interleukin-10, the presence of antibody to transforming growth factor beta and interleukin-10 had no effect on the suppressive effect of CD4⁺CD25⁺ regulatory T cells on CD8⁺ T-cell proliferation. In conclusion, marked CD4⁺CD25⁺ regulatory T-cell activity is present in patients with chronic HCV infection, which may contribute to weak HCV-specific CD8⁺ T-cell responses and viral persistence.

These authors contributed equally to this work.

Present address: Centre for Clinical Immunology and Biomedical Statistics, Murdoch University, Second Floor, North Block, Royal Perth Hospital, Perth 6000, Australia.

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