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Journal of Virology, September 2009, p. 9122-9130, Vol. 83, No. 18
0022-538X/09/$08.00+0     doi:10.1128/JVI.00639-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Negative Immune Regulator Tim-3 Is Overexpressed on T Cells in Hepatitis C Virus Infection and Its Blockade Rescues Dysfunctional CD4+ and CD8+ T Cells{triangledown}

Lucy Golden-Mason,1 Brent E. Palmer,2 Nasim Kassam,3 Lisa Townshend-Bulson,4 Stephen Livingston,4 Brian J. McMahon,4,5 Nicole Castelblanco,1 Vijay Kuchroo,3 David R. Gretch,6 and Hugo R. Rosen1*

Department of Medicine, Division of Gastroenterology and Hepatology, University of Colorado Health Sciences Center and National Jewish Hospital, and Denver VA Center, Denver, Colorado,1 Division of Clinical Immunology, University of Colorado Health Sciences Center and National Jewish Hospital, Denver, Colorado,2 Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115,3 Alaska Native Tribal Health Consortium; Liver Disease and Hepatitis Program, Anchorage, Alaska,4 Arctic Investigations Program, Division of Emerging Infections and Surveillance Services, National Center for Preparedness, Detection and Control of Infectious Diseases, Centers for Disease Control and Prevention, Anchorage, Alaska,5 Division of Laboratory Medicine, University of Washington, Seattle, Washington6

Received 27 March 2009/ Accepted 19 June 2009

A number of emerging molecules and pathways have been implicated in mediating the T-cell exhaustion characteristic of chronic viral infection. Not all dysfunctional T cells express PD-1, nor are they all rescued by blockade of the PD-1/PD-1 ligand pathway. In this study, we characterize the expression of T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) in chronic hepatitis C infection. For the first time, we found that Tim-3 expression is increased on CD4+ and CD8+ T cells in chronic hepatitis C virus (HCV) infection. The proportion of dually PD-1/Tim-3-expressing cells is greatest in liver-resident T cells, significantly more so in HCV-specific than in cytomegalovirus-specific cytotoxic T lymphocytes. Tim-3 expression correlates with a dysfunctional and senescent phenotype (CD127low CD57high), a central rather than effector memory profile (CD45RAnegative CCR7high), and reduced Th1/Tc1 cytokine production. We also demonstrate the ability to enhance T-cell proliferation and gamma interferon production in response to HCV-specific antigens by blocking the Tim-3-Tim-3 ligand interaction. These findings have implications for the development of novel immunotherapeutic approaches to this common viral infection.

* Corresponding author. Mailing address: GI and Hepatology Division, B-158, Academic Office Building 1, 12631 East 17th Avenue, Room 7614, P.O. Box 6511, Aurora, CO 80045. Phone: (303) 724-1858. Fax: (303) 724-1891. E-mail: Hugo.Rosen{at}UCHSC.edu

{triangledown} Published ahead of print on 8 July 2009.

Journal of Virology, September 2009, p. 9122-9130, Vol. 83, No. 18
0022-538X/09/$08.00+0     doi:10.1128/JVI.00639-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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