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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,{dagger} Scott M. Ward,2,{dagger} Esther Unitt,1 Sarah L. Vowler,3 Michaela Lucas,2,{ddagger} 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 (Treg) 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-{gamma}) frequency were analyzed with/without depletion of Treg cells, using peptides derived from HCV, Epstein-Barr virus (EBV), and cytomegalovirus (CMV). CD4+CD25+ Treg cells inhibited anti-CD3/CD28 CD8+ T-cell proliferation and perforin expression. Depletion of CD4+CD25+ Treg 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-{gamma}-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.

* Corresponding author. Mailing address: Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford, South Parks Road, Oxford OX1 3SY, United Kingdom Phone: 44 1865 281885. Fax: 44 1865 281890. E-mail: paul.klenerman{at}medawar.ox.ac.uk.

{dagger} These authors contributed equally to this work.

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

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.



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