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Journal of Virology, May 2008, p. 5043-5053, Vol. 82, No. 10
0022-538X/08/$08.00+0     doi:10.1128/JVI.01548-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Identification and In Vitro Expansion of Functional Antigen-Specific CD25+ FoxP3+ Regulatory T Cells in Hepatitis C Virus Infection{triangledown}

Hirotoshi Ebinuma,1,2,{dagger} Nobuhiro Nakamoto,1,2,{dagger} Yun Li,1,2 David A. Price,3 Emma Gostick,3 Bruce L. Levine,2 J. Tobias,2 William W. Kwok,4 and Kyong-Mi Chang1,2*

Philadelphia VAMC, Philadelphia, Pennsylvania,1 University of Pennsylvania, Philadelphia, Pennsylvania,2 Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom,3 Benaroya Institute at Virginia Mason, Seattle, Washington4

Received 16 July 2007/ Accepted 4 March 2008

CD4+CD25+ regulatory T cells (CD25+ Tregs) play a key role in immune regulation. Since hepatitis C virus (HCV) persists with increased circulating CD4+CD25+ T cells and virus-specific effector T-cell dysfunction, we asked if CD4+CD25+ T cells in HCV-infected individuals are similar to natural Tregs in uninfected individuals and if they include HCV-specific Tregs using the specific Treg marker FoxP3 at the single-cell level. We report that HCV-infected patients display increased circulating FoxP3+ Tregs that are phenotypically and functionally indistinguishable from FoxP3+ Tregs in uninfected subjects. Furthermore, HCV-specific FoxP3+ Tregs were detected in HCV-seropositive persons with antigen-specific expansion, major histocompatibility complex class II/peptide tetramer binding affinity, and preferential suppression of HCV-specific CD8 T cells. Transforming growth factor β contributed to antigen-specific Treg expansion in vitro, suggesting that it may contribute to antigen-specific Treg expansion in vivo. Interestingly, FoxP3 expression was also detected in influenza virus-specific CD4 T cells. In conclusion, functionally active and virus-specific FoxP3+ Tregs are induced in HCV infection, thus providing targeted immune regulation in vivo. Detection of FoxP3 expression in non-HCV-specific CD4 T cells suggests that immune regulation through antigen-specific Treg induction extends beyond HCV.

* Corresponding author. Mailing address: Division of Gastroenterology, Department of Medicine, Philadelphia Veterans Affairs Medical Center and University of Pennsylvania, VA Medical Research, University and Woodland Avenue, Philadelphia, PA 19104. Phone: (215) 823-5893. Fax: (215) 823-4394. E-mail: kmchang{at}mail.med.upenn.edu

{triangledown} Published ahead of print on 12 March 2008.

{dagger} Hirotoshi Ebinuma and Nobuhiro Nakamoto share first coauthorship with equal contribution.

Journal of Virology, May 2008, p. 5043-5053, Vol. 82, No. 10
0022-538X/08/$08.00+0     doi:10.1128/JVI.01548-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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