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Journal of Virology, March 2007, p. 2940-2949, Vol. 81, No. 6
0022-538X/07/$08.00+0     doi:10.1128/JVI.02415-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The Level of Viral Antigen Presented by Hepatocytes Influences CD8 T-Cell Function{triangledown}

Adam J. Gehring,1,4,{dagger} Dianxing Sun,2 Patrick T. F. Kennedy,1 Esther Nolte-'t Hoen,3 Seng Gee Lim,5 Shanthi Wasser,5 Clare Selden,1 Mala K. Maini,6 Dan M. Davis,3 Michael Nassal,2 and Antonio Bertoletti1,4*

UCL Institute of Hepatology, Royal Free and University College Medical School, London, United Kingdom,1 Internal Medicine II and Molecular Biology, University Hospital Freiburg, Freiburg, Germany,2 Division of Cell and Molecular Biology, Imperial College, London, United Kingdom,3 Center for Molecular Medicine, Agency for Science Technology and Research, Singapore,4 Department of Medicine, National University Singapore, Singapore,5 Division of Infection and Immunity, University College London, London, United Kindgom6

Received 3 November 2006/ Accepted 20 December 2006

CD8 T cells exert their antiviral function through cytokines and lysis of infected cells. Because hepatocytes are susceptible to noncytolytic mechanisms of viral clearance, CD8 T-cell antiviral efficiency against hepatotropic viruses has been linked to their capacity to produce gamma interferon (IFN-{gamma}) and tumor necrosis factor alpha (TNF-{alpha}). On the other hand, intrahepatic cytokine production triggers the recruitment of mononuclear cells, which sustain acute and chronic liver damage. Using virus-specific CD8 T cells and human hepatocytes, we analyzed the modulation of virus-specific CD8 T-cell function after recognition peptide-pulsed or virally infected hepatocytes. We observed that hepatocyte antigen presentation was generally inefficient, and the quantity of viral antigen strongly influenced CD8 T-cell antiviral function. High levels of hepatitis B virus production induced robust IFN-{gamma} and TNF-{alpha} production in virus-specific CD8 T cells, while limiting amounts of viral antigen, both in hepatocyte-like cells and naturally infected human hepatocytes, preferentially stimulated CD8 T-cell degranulation. Our data document a mechanism where virus-specific CD8 T-cell function is influenced by the quantity of virus produced within hepatocytes.

* Corresponding author. Present address: Center for Molecular Medicine, NUH Main Building, Gastro Lab 02-512, 5 Lower Kent Ridge Road, Singapore 119074. Phone: 65 6772 2301. Fax: 65 6772 4087. E-mail: antonio{at}cmm.a-star.edu.sg.

{triangledown} Published ahead of print on 3 January 2007.

{dagger} Present address: Center for Molecular Medicine, NUH Main Building, Gastro Lab 02-512, 5 Lower Kent Ridge Road, Singapore 119074.

Journal of Virology, March 2007, p. 2940-2949, Vol. 81, No. 6
0022-538X/07/$08.00+0     doi:10.1128/JVI.02415-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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