Decrease in hepatic CD56 1 T cells and Va24 1 natural killer T cells in chronic hepatitis C viral infection Tina Deignan 1,† , Michael P. Curry 1,2,† , Derek G. Doherty 1,3 , Lucy Golden-Mason 1 , Yuri Volkov 4 , Suzanne Norris 5 , Niamh Nolan 6 , Oscar Traynor 2 , Gerry McEntee 2 , John E. Hegarty 2,7,†† , Cliona O’Farrelly 1,7,††, * 1 Education and Research Centre, St. Vincent’s University Hospital, Elm Park, Dublin 4, Ireland 2 Liver Unit, St. Vincent’s University Hospital, Dublin, Ireland 3 Institute of Immunology & Department of Biology, National University of Ireland, Maynooth, Ireland 4 Department of Clinical Medicine, Trinity College, Dublin, Ireland 5 Institute of Liver Studies, King’s Healthcare, London, UK 6 Department of Pathology, St. Vincent’s University Hospital, Dublin, Ireland 7 The Conway Institute, University College Dublin, Dublin, Ireland Background/Aims: The intrahepatic immune system is likely to play a key role in determining the outcome of hepatitis C virus (HCV) infection. The hepatic lymphocyte repertoire is characterised by high CD8/CD4 T cell ratios and large numbers of gd T cells, natural killer (NK) cells, NK T cells and NK receptor-positive T cells. It is not known which of these populations contribute to immunity against HCV or immune pathology. Methods: To explore the relative contributions of lymphocyte subpopulations, we have compared the intrahepatic lymphocyte repertoires and cytokine expression in 13 patients with mild chronic hepatitis C infection, 14 with end-stage hepatitis C cirrhosis and five histologically normal livers by flow cytometry and immunohistochemistry. Results: CD4 1 T cells bearing ab T cell receptors (TCR) were significantly expanded in livers with chronic HCV infection while CD56 1 ab T cells and Va24 TCR-positive T cells were significantly depleted. Expanded CD4 1 T cells were predominantly Th1 cells, producing interferon-g but not interleukin-4. Conclusions: Failure to resolve HCV infection may be due to deficient innate and/or memory immune responses, while Th1 cells may mediate immune pathology. q 2002 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved. Keywords: Natural killer cells; Hepatitis C virus; T cell receptor 1. Introduction Hepatitis C virus (HCV) infects over 170 million people worldwide [1]. A minority (,20%) resolve acute hepatitis and clear the virus, but most develop life-long infection, making HCV a leading cause of chronic liver disease, cirrhosis and hepatocellular carcinoma [1,2]. The host immune response to HCV antigens is thought to determine whether viral clearance or chronicity occurs. Studies in chimpanzees (the only animal model for HCV infection) suggest that resolution or persistence of HCV infection depends on the strength of intrahepatic lymphocyte responses that are generated at the early stages of acute hepatitis [4]. Analyses of peripheral HCV-specific T cell responses in humans support this notion [5]. In contrast, chronicity of HCV infection is associated with weaker early HCV-specific T cell responses and a persistence of responses that contribute to liver damage [3–5]. The intrahepatic immune system is characterised by a unique repertoire of lymphocytes [6,7]. In addition to conventional CD4 1 and CD8 1 T cells and B cells, the liver contains large numbers of natural killer (NK) cells, Journal of Hepatology 37 (2002) 101–108 0168-8278/02/$20.00 q 2002 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved. PII: S0168-8278(02)00072-7 www.elsevier.com/locate/jhep Received 4 October 2001; received in revised form 28 February 2002; accepted 4 March 2002 * Corresponding author. Tel.: 1353-1-2094940; fax: 1353-1-2838123. E-mail address: cliona.ofarrelly@ucd.ie (C. O’Farrelly). † Contributed equally to this study. †† Contributed equally to the direction of this study.