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¹ Division of Infection and Immunity, ² Institute of Hepatology, ³ Camden Primary Care Trust and Centre for Sexual Health and HIV, University College London, London W1T 4JF, England, UK
⁴ Department of Medicine, Addenbrooke's Hospital Cambridge, Cambridge CB2 2QQ, England, UK
⁵ UCB Celltech, Berkshire SL1 4EN, England, UK
⁶ Singapore Institute for Clinical Sciences, Agency for Science Technology and Research, Singapore 138632

CORRESPONDENCE Mala K. Maini: m.maini{at}ucl.ac.uk

The inflamed liver in chronic hepatitis B virus (HBV) infection (CHB) is characterized by a large influx of non–virus-specific CD8 T cells. Little is known about the functional capacity of these lymphocytes, which could provide insights into mechanisms of failure of viral control and liver damage in this setting. We compared the effector function of total circulating and intrahepatic CD8 T cells in CHB patients and healthy donors. We demonstrated that CD8 T cells from CHB patients, regardless of their antigen specificity, were impaired in their ability to produce interleukin-2 and proliferate upon TCR-dependent stimulation. In contrast, these CD8 T cells had preserved production of the proinflammatory cytokines interferon- and tumor necrosis factor-. This aberrant functional profile was partially attributable to down-regulation of the proximal T cell receptor signaling molecule CD3, and could be corrected in vitro by transfection of CD3 or replenishment of the amino acid arginine required for its expression. We provide evidence for depletion of arginine in the inflamed hepatic microenvironment as a potential mechanism for these defects in global CD8 T cell signaling and function. These data imply that polarized CD8 T cells within the HBV-infected liver may impede proliferative antiviral effector function, while contributing to the proinflammatory cytokine environment.

© 2008 Das et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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Hema Bashyam
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