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Blood, 1 May 2005, Vol. 105, No. 9, pp. 3605-3614.
Prepublished online as a Blood First Edition Paper on January 18, 2005; DOI 10.1182/blood-2004-05-1952.
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IMMUNOBIOLOGY
Uptake and presentation of hepatitis C virus–like particles by human dendritic cells
Heidi Barth,
Axel Ulsenheimer,
Gerd R. Pape,
Helmut M. Diepolder,
Marco Hoffmann,
Christoph Neumann-Haefelin,
Robert Thimme,
Philipp Henneke,
Reinhild Klein,
Glaucia Paranhos-Baccalà,
Erik Depla,
T. Jake Liang,
Hubert E. Blum, and
Thomas F. Baumert
From the Department of Medicine II, University of Freiburg, Freiburg, Germany; Department of Medicine II, Klinikum Grosshadern, University of Munich, Munich, Germany; Children's Hospital, University of Freiburg, Freiburg, Germany; Department of Medicine II, University of Tübingen, Tübingen, Germany; Centre National de la Recherche Scientifique (CNRS)-bioMérieux-Centre d'Etudes et de Recherches en Virologie et Immunologie (CERVI)-Institut Fédératif de Recherche 128 (IFR128), Lyon, France; Innogenetics NV, Ghent, Belgium; and Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), Bethesda, MD.
Hepatitis C virus (HCV) is a major cause of chronic hepatitis worldwide. Interaction of dendritic cells (DCs) with viral particles may play an important role in the immunopathogenesis of HCV infection. Since the synthesis or purification of infectious virions is limited, we used HCV-like particles (HCV-LPs) to study the interaction of HCV with human DCs. Immature DCs exhibited an envelope-specific and saturable binding of HCV-LPs, indicating receptor-mediated DC–HCV-LP interaction. Confocal microscopy revealed that HCV-LPs were rapidly taken up by DCs in a temperature-dependent manner. Competition experiments demonstrated that C-type lectins such as mannose receptor or DC-SIGN (DC–specific intercellular adhesion molecule 3–grabbing nonintegrin) were not sufficient for mediating HCV-LP binding. HCV-LP uptake was followed by DC activation. DCs pulsed with HCV-LPs stimulated HCV core-specific CD4+ T cells, indicating that uptake of HCV-LPs by DCs leads to antigen processing and presentation on major histocompatibility complex (MHC) class II molecules. Finally, HCV-LP–derived antigens were efficiently cross-presented to HCV core-specific CD8+ T cells. These findings demonstrate that HCV-LPs represent a novel model system to study HCV-DC interaction allowing definition of the molecular mechanisms of HCV uptake, DC activation, and antigen presentation to T cells. Furthermore, HCV-LP–mediated DC activation and efficient antigen presentation may explain the marked immunogenicity of HCV-LPs in vivo.
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