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Journal of Virology, June 2005, p. 7860-7867, Vol. 79, No. 12
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.12.7860-7867.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

T Cells with a CD4+CD25+ Regulatory Phenotype Suppress In Vitro Proliferation of Virus-Specific CD8+ T Cells during Chronic Hepatitis C Virus Infection

Tobias Boettler,1,{dagger} Hans Christian Spangenberg,1,{dagger} Christoph Neumann-Haefelin,1 Elisabeth Panther,1 Simonetta Urbani,2 Carlo Ferrari,2 Hubert E. Blum,1 Fritz von Weizsäcker,1 and Robert Thimme1*

Department of Medicine II, University Hospital Freiburg, Freiburg,Germany,1 Division of Infectious Diseases and Hepatology, University of Parma, Parma, Italy2

Received 12 October 2004/ Accepted 7 February 2005

Chronic hepatitis C virus (HCV) infection is associated with impaired proliferative, cytokine, and cytotoxic effector functions of HCV-specific CD8+ T cells that probably contribute significantly to viral persistence. Here, we investigated the potential role of T cells with a CD4+CD25+ regulatory phenotype in suppressing virus-specific CD8+ T-cell proliferation during chronic HCV infection. In vitro depletion studies and coculture experiments revealed that peptide specific proliferation as well as gamma interferon production of HCV-specific CD8+ T cells were inhibited by CD4+CD25+ T cells. This inhibition was dose dependent, required direct cell-cell contact, and was independent of interleukin-10 and transforming growth factor beta. Interestingly, the T-cell-mediated suppression in chronically HCV-infected patients was not restricted to HCV-specific CD8+ T cells but also to influenza virus-specific CD8+ T cells. Importantly, CD4+CD25+ T cells from persons recovered from HCV infection and from healthy blood donors exhibited significantly less suppressor activity. Thus, the inhibition of virus-specific CD8+ T-cell proliferation was enhanced in chronically HCV-infected patients. This was associated with a higher frequency of circulating CD4+CD25+ cells observed in this patient group. Taken together, our results suggest that chronic HCV infection leads to the expansion of CD4+CD25+ T cells that are able to suppress CD8+ T-cell responses to different viral antigens. Our results further suggest that CD4+CD25+ T cells may contribute to viral persistence in chronically HCV-infected patients and may be a target for immunotherapy of chronic hepatitis C.

* Corresponding author. Mailing address: Department of Medicine II, University Hospital Freiburg, Hugstetter Strasse 55, D-79106 Freiburg, Germany. Phone: 49-761-270 3280. Fax: 49-761-270 3372. E-mail: thimme{at}med1.ukl.uni-freiburg.de.

{dagger} Equal contribution.

Journal of Virology, June 2005, p. 7860-7867, Vol. 79, No. 12
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.12.7860-7867.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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