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Journal of Virology, December 2008, p. 11742-11748, Vol. 82, No. 23
0022-538X/08/$08.00+0     doi:10.1128/JVI.01130-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Hepatitis C Virus-Specific T-Cell Gamma Interferon and Proliferative Responses Are More Common in Perihepatic Lymph Nodes than in Peripheral Blood or Liver{triangledown}

Dilip Moonka,1 Kimberly A. Milkovich,2 Benigno Rodriguez,2 Marwan Abouljoud,1 Michael M. Lederman,2 and Donald D. Anthony2*

Division of Gastroenterology, Transplant Surgery, Henry Ford Health System, Detroit, Michigan,1 Department of Medicine, Divisions of Infectious and Rheumatic Diseases, Case Western Reserve University, University Hospitals of Cleveland, Center for AIDS Research and VA Medical Center, Cleveland, Ohio2

Received 29 May 2008/ Accepted 8 August 2008

The activation state, differentiation state, and functions of liver lymphocytes and perihepatic lymph nodes during chronic hepatitis C virus (HCV) infection are not well understood. Here, we performed phenotypic and functional analyses of freshly prepared lymphocytes isolated from the livers, perihepatic lymph nodes, and peripheral blood compartments of chronic HCV-infected and disease control subjects with end-stage liver disease undergoing liver transplantation. We measured lymphocyte subset frequency and memory T-cell gamma interferon (IFN-{gamma}) and proliferative responses to HCV peptide and control viral antigens in direct ex vivo assays. We found higher frequencies of CD4 cells in the lymph node compartment than in the other compartments for both HCV-infected and disease control subjects. Lymph node CD4 and CD8 cells less commonly expressed the terminal differentiation marker CD57, a finding consistent with an earlier differentiation state. In HCV-infected subjects, HCV-specific IFN-{gamma}-producing and proliferative responses were commonly observed in the lymph node fraction, while they were uncommonly observed in the peripheral blood or liver fractions. In contrast, control viral CD4 protein antigen and CD8 peptide antigen-specific IFN-{gamma} responses were commonly observed in the periphery and uncommonly observed in the lymph nodes of these same subjects. These findings are consistent with a selective defect in HCV-specific T-cell effector function or distribution in patients with advanced chronic HCV infection. The high frequency of HCV-reactive T cells in perihepatic lymph nodes indicates that a failure to generate or sustain T-lymphocyte HCV reactivity is not responsible for the paucity of functional cells even in end-stage liver disease.

* Corresponding author. Mailing address: Biomedical Research Building 1028, Case Western Reserve University, 2109 Adelbert Rd., Cleveland, OH 44106. Phone: (216) 368-3540. Fax: (216) 368-2034. E-mail: DDA3{at}CASE.EDU

{triangledown} Published ahead of print on 20 August 2008.

Journal of Virology, December 2008, p. 11742-11748, Vol. 82, No. 23
0022-538X/08/$08.00+0     doi:10.1128/JVI.01130-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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