Hepatology
Viral Hepatitis
CD161 expression on hepatitis C virus–specific CD8+ T cells suggests a distinct pathway of T cell differentiation
Northfield, John W.1; Kasprowicz, Victoria2; Lucas, Michaela3; Kersting, Nadine4; Bengsh, Bertram4; Kim, Arthur2; Phillips, Rodney E.1; Walker, Bruce D.2; Thimme, Robert4; Lauer, Georg2; Klenerman, Paul1*
1Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK
2Partners AIDS Research Group, Charlestown, MA
3Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital, Perth, Australia
4Department of Medicine II, University of Freiburg, Freiburg, Germany
*Address reprint requests to: Peter Medawar Building for Pathogen Research, University of Oxford, South Parks Road, Oxford, OX13SY, UK
Email:[email protected]
Received 20 April 2007; Accepted 11 September 2007
Published online in Wiley InterScience (www.interscience.wiley.com).
Grant sponsor: Wellcome Trust; Grant sponsor: Deutsche Forschungsgemeinschaft; Grant sponsor: American Liver Foundation; Grant sponsor: NIH; Grant Numbers: A1066345 A107433.
These authors contributed equally to this study.
Potential conflict of interest: Dr. Klenerman is a consultant for Intercell.
fax: (44) 1865-281236.
Abstract
Hepatitis C virus (HCV) causes chronic infection accompanied by a high risk of liver failure and hepatocellular carcinoma. CD8+ T cell responses are important in the control of viremia. However, the T cell response in chronic infection is weak both in absolute numbers and in the range of epitopes targeted. In order to explore the biology of this response further, we analyzed expression of a panel of natural killer cell markers in HCV compared with other virus-specific T cell populations as defined by major histocompatibility complex class I tetramers. We found that CD161 was significantly expressed on HCV-specific cells (median 16.8%) but not on CD8+ T cells specific for human immunodeficiency virus (3.3%), cytomegalovirus (3.4%), or influenza (3.4%). Expression was seen in acute, chronic, and resolved disease and was greatest on intrahepatic HCV-specific T cells (median 57.6%;P< 0.05). Expression of CD161 was also found on hepatitis B virus–specific CD8+ T cells. In general, CD161+CD8+ T cells were found to be CCR7− “effector memory” T cells that could produce proinflammatory cytokines (interferon-γ and tumor necrosis factor-α) but contained scanty amounts of cytolytic molecules (granzyme B and perforin) and proliferated poorly in vitro. Expression of CD161 on CD8+ T cells was tightly linked to that of CXCR6, a chemokine with a major role in liver homing.Conclusion:We propose that expression of CD161 indicates a unique pattern of T cell differentiation that might help elucidate the mechanisms of HCV immunity and pathogenesis. (Hepatology 2008;47:396–406.)
Abbreviations: CMV, cytomegalovirus; FACS, fluorescence-activated cell sorting; FITC, fluorescein isothiocyanate; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IFN-γ, interferon-γ; IL, interleukin; NK, natural killer; PBMC, peripheral blood mononuclear cell; PE, phycoerythrin; SE, standard error; TGF-β, transforming growth factor-β.