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JVI Accepts, published online ahead of print on 20 December 2006
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J. Virol. doi:10.1128/JVI.02021-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Liver infiltrating lymphocytes in chronic human HCV infection display an exhausted phenotype with high PD-1 and low CD127 expression

Henry Radziewicz, Chris C. Ibegbu, Marina L. Fernandez, Kimberly A. Workowski, Kamil Obideen, Mohammad Wehbi, Holly L. Hanson, James P. Steinberg, David Masopust, E. John Wherry, John D. Altman, Barry T. Rouse, Gordon J. Freeman, Rafi Ahmed, and Arash Grakoui*

Emory Vaccine Center and Department of Microbiology and Immunology, and Department of Medicine, Emory University School of Medicine, Atlanta, GA, 30322; Immunology Program, The Wistar Institute, Philadelphia, PA 19104; College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996; Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02115

* To whom correspondence should be addressed. Email: arash.grakoui{at}emory.edu.


  Abstract

The majority of people infected with hepatitis C virus (HCV) fail to generate or maintain a T cell response effective for viral clearance. Evidence from murine chronic viral infections shows that expression of the co-inhibitory molecule PD-1 predicts CD8+ antiviral T cell exhaustion and may contribute to inadequate pathogen control. To investigate whether human CD8+ T cells express PD-1 and demonstrate a dysfunctional phenotype during chronic HCV infection, peripheral and intrahepatic HCV-specific CD8+ T cells were examined. We found that in chronic HCV infection, peripheral HCV-specific T cells express high levels of PD-1 and that blockade of the PD-1/PD-L1 interaction led to an enhanced proliferative capacity. Importantly, intrahepatic HCV-specific T cells, in contrast to those in the periphery, not only express high levels of PD-1 but also decreased IL-7 receptor alpha (CD127), an exhausted phenotype that was HCV antigen specific and compartmentalized to the liver, the site of viral replication.




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