Introduction Hepatitis C Virus (HCV) is a major cause of liver disease worldwide. Innate and adaptive cellular immune responses play a critical role in resolving acute HCV infection. However, the majority of infections are not cleared, resulting in a progressive chronic liver disease consistent with inadequate immune control. Evidence from human and animal models suggest that T cells play a critical role in controlling acute HCV infection, yet the mechanism(s) behind their failure to control chronic HCV replication are unknown. HCV replicates predominantly in the liver and virus specific immune cells need to target infected hepatocytes to control virus replication. HCV specific effector cells have been reported to home to the liver, however, little is known on their subsequent trafficking and fate within the organ.
Aim Our aim is to investigate the role of HCV infection on lymphocyte-hepatocyte interactions, migration and immune cell effector function.
Method We used in vitro and ex vivo models to study the effect of HCV infection on lymphocyte–hepatocyte interactions. Primary lymphocytes and hepatocytes were used in combination with hepatoma cell lines and replication competent HCV clones. Ex vivo lymphocyte migration assays were performed using biopsy material and tissue from explanted liver. Results were confirmed by in vivo observations using tissue sections from patients with end stage liver disease of viral and non-viral origin. Experimental techniques included immunohistochemistry, flow cytometry, fixed and live cell time-lapse confocal microscopy.
Results We demonstrate: (1) A role for hepatocyte ICAM-1 in mediating T-lymphocyte adhesion and migration; (2) T-lymphocytes migrate spontaneously through hepatocyte monolayers via cell-cell junctions; (3). HCV enhances T-cell transmigration and pro-inflammatory cytokine expression. Our data demonstrate the existence of novel interactions between T cells and hepatocytes that are modulated in HCV infection. The nature of the T cell-hepatocyte interactions may have an impact on T-cell effector function and the outcome of anti-viral immune responses.
Conclusion Interaction with HCV-infected hepatocytes alters T-cell trafficking and cytokine expression, providing a novel mechanism for HCV to persist in the liver.
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