The phenotype of hepatitis B virus–specific T cells differ... : Hepatology (original) (raw)

Viral Hepatitis

The phenotype of hepatitis B virus–specific T cells differ in the liver and blood in chronic hepatitis B virus infection

Chang, Judy J.1; Thompson, Alexander J. V.2,3; Visvanathan, Kumar4; Kent, Stephen J.1,5; Cameron, Paul U.4,5; Wightman, Fiona4; Desmond, Paul3; Locarnini, Stephen A.2; Lewin, Sharon R.1,4,5*

1_Department of Microbiology and Immunology, University of Melbourne, Australia_

2_Victorian Infectious Diseases Reference Laboratory, Australia_

3_Department of Gastroenterology, St Vincent's Hospital, Australia_

4_Department of Medicine, Monash University, Australia_

5_Infectious Diseases Unit, Alfred Hospital, Victoria, Australia_

*Address reprint requests to: Infectious Diseases Unit, Alfred Hospital, Commercial Road, Melbourne, VIC 3004, Australia

Email:[email protected]

Received 11 April 2007; Accepted 30 May 2007

Published online 8 October 2007 in Wiley InterScience (www.interscience.wiley.com).

Grant sponsor: U.S. National Institutes of Health; Grant Number: NIH R21 AI055379-01 A1; Grant sponsor: Australian Postgraduate Awards; Grant sponsor: Alfred Foundation; Grant sponsor: National Health and Medicine Research Council (NHMRC) Practitioner Fellow; Grant Number: #251651.

Potential conflict of interest: Dr. Locarnini is a consultant for and owns stock in Pharmasset. He is also a consultant for Evivar Pty., Ltd., Innogenetics, Melbourne Health, Gilead, Bristol-Myers Squibb, and LG Sciences.

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Abstract

Hepatitis B virus (HBV)-specific T cells play a key role in clearance of the virus and in the pathogenesis of liver disease. Peripheral blood (n = 25) and liver biopsies (n = 19) were collected from individuals with chronic untreated HBV infection. Whole blood, cultured peripheral blood mononuclear cells (PBMCs), and cultured liver-infiltrating lymphocytes (LILs) were each stimulated with an overlapping peptide library to the whole HBV genome. The expression of T helper 1 (Th1) cytokines [interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukin 2 (IL-2)] and interleukin 10 (IL-10) was analyzed by intracellular cytokine staining and flow cytometry. In ex vivo whole blood, more lymphocytes produced Th1 cytokines than IL-10. When comparing cultured LILs with cultured PBMCs, we found a significantly higher magnitude of CD8+ T cells from the liver producing IL-10 ( P = 0.044), primarily in hepatitis B e antigen positive (HBeAg+) individuals. A positive correlation resulted between the magnitude of HBV-specific TNF-α+ CD4+ T cells in the liver and the degree of liver inflammation and fibrosis ( P = 0.002 and P = 0.006, respectively).

Conclusion:

The differences in cytokine production from HBV-specific T cells in blood and liver may explain the capacity for HBV to persist in the absence of significant hepatic destruction and highlights the balance between cytokine-mediated viral control and liver damage.

Abbreviations: ALT, alanine aminotransferase; cccDNA, covalently closed circular DNA; HBeAg, precore antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; ICS, intracellular staining; IFN-γ interferon gamma; IL-2, interleukin-2; IL-10, interleukin-10; LIL, liver infiltrating lymphocytes; NKT, natural killer T; OR, odds ratio; PBMC, peripheral blood mononuclear cells; TNF-α tumor necrosis factor alpha.