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

Abstract

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-␥) 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-␥-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-␥ 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.During hepatitis C virus (HCV) infection, both CD4 and CD8 virus-specific lymphocytes are thought to play important roles both in control/clearance of viral infection and in hepatocellular damage (7,9,13,23,26,32,33,37,38,40). Priming of these cells during acute infection and sustained activation of memory cells during chronic infection are thought to take place in regional lymph nodes that drain the tissue sites of infection. Chronic HCV infection is characterized by low frequencies of HCV-reactive T cells in circulation (16,34,(42)(43)(44). While there are a number of potential explanations for these meager responses, the relative distribution levels of HCVreactive T cells in lymph nodes, liver, and peripheral blood are not well recognized. We therefore examined the phenotype and function of HCV-specific T cells within the regional lymph nodes, livers, and peripheral blood of HCV-infected individuals, using freshly isolated tissue samples in order to obtain an improved understanding of the dominant T-cell dynamics during HCV infection and to establish a foundation for improved models of compartmentalized T-cell activation during chronic viral hepatitis. Results indicate similar paucities of functional HCV-specific T cells in the liver and periphery, while HCVreactive T cells ar...

Adaptive Immunity to the Hepatitis C Virus

“…How T cells targeting intact and mutated epitopes survive in the persistently infected liver without any apparent mechanism for self-renewal is uncertain but probably depends on constant stimulation with HCV antigens. One intriguing possibility is that lymph nodes draining the liver are a site of CD8+ T cell renewal in chronic hepatitis C. Perihepatic lymph nodes from individuals with advanced hepatitis C were recently shown to harbor HCV-specific CD8+ T cells that appeared to retain effector functions when compared with those in the liver and blood (Moonka et al , 2008). …”

Disappearance of perihepatic lymph node enlargement after hepatitis C viral eradication with direct‐acting antivirals

“…Perihepatic lymph node enlargement was shown to reflect the immunological response of the host, especially in CHC patients . Indeed, HCV‐specific IFN‐γ production and proliferative responses of T cells were found commonly in perihepatic lymph nodes, suggesting that PLNE indicates an active host immune response in chronic hepatitis C. In the present study, baseline HCV‐RNA level was significantly suppressed and AST or ALT levels were higher in patients with PLNE. These findings may reflect higher immune responses against HCV in patients who are PLNE‐positive.…”

A spatial view of the CD8+ T‐cell response: the case of HCV

“…HCV‐specific CD8 + T cells have been detected in perihepatic lymph nodes and bone marrow of patients with persistent HCV infection. Data on this matter come from only two papers and therefore are too scanty to draw definitive conclusions.…”

“…Perihepatic lymph nodes, the likely site of HCV‐specific T cell priming, hold a large number of HCV‐specific T cells that are CD57 − and produce more IFN‐γ than their blood and liver equivalents upon in vitro stimulation with HCV peptide pools. These qualities are consistent with a “T CM ‐like” phenotype, which is typical of secondary lymphoid organ . Bone marrow, which is neither a site of HCV infection nor a conventional secondary lymphoid organ, has been found to contain an HCV‐specific CD8 + T‐cell population 25 times greater than that in the blood and two times greater than that in the liver.…”