Parenchymal expression of CD86/B7.2 contributes to hepatitis C virus-related liver injury

Liver disease due to hepatitis C virus (HCV) infection is an emerging public health problem, as persistent viral infection leads to liver cirrhosis and cancer in some patients (63a). No vaccine for prevention of HCV infection exists, and current interferon-based therapies result in a sustained antiviral response in only about 50% of patients (39). The mechanisms of pathogenesis are not fully understood. Since immune-based therapies that could improve viral clearance and reduce disease progression in chronically infected individuals would be of great benefit (21, 41, 65), a better understanding of the mechanisms contributing to liver injury and T-cell clearance of HCV infection are important goals for HCV research. The body maintains tolerance to many gut-derived antigens (54). Although the mechanisms underlying this process remain unclear, it is thought that immune responses within the liver are associated with tolerance. In the liver, hepatocytes express low levels of major histocompatibility complex (MHC) and virtually no immune costimulatory molecules (such as CD80/B7.1, CD86/B7.2, and CD40). These conditions ensure that T cells “ignore” antigens expressed by the parenchymal cells. To mount an efficient immune response, costimulatory molecules on antigen-presenting cells need to engage their ligands on T cells, and this interaction provides a crucial signal permitting the activation and differentiation of T cells into effector cells. In human HCV infection, high levels of MHC class II and costimulatory molecules are expressed on the activated Kupffer cells and hepatocytes, and their levels are also correlated with the extent of intrahepatic inflammation and elevation of serum alanine aminotransferase (ALT) a biochemical marker of liver injury (10, 37). Despite this association between costimulatory molecules and these clinical parameters of disease, the functional relationship between expression of these molecules and HCV-related liver injury has not been directly examined, partly due to a lack of suitable animal models. To examine the pathogenesis of HCV in vivo, several groups have established transgenic mice that constitutively express HCV proteins in the liver and have found increased micro- and macrovesicular hepatic steatosis and an increased incidence of hepatocellular carcinoma in these animals (32, 38, 55). However, since the constitutive expression of HCV proteins begins in utero in these mice, they do not develop HCV-specific cellular responses or hepatic inflammation due to immune tolerance to the HCV antigens. To overcome this obstacle, we developed transgenic mouse lineages with inducible expression of HCV structural proteins and/or constitutive expression of the costimulatory molecule CD86/B7.2 in the liver, and we investigated the relationship between costimulatory signaling molecule CD86 expression and HCV-related hepatic inflammation in double-transgenic animals. Using a hydrodynamic-based, nonviral delivery protocol (33), we induced expression of the HCV transgene in mouse liver with Cre DNA recombinase (30) and found that animals coexpressing CD86 developed more pronounced inflammatory responses within the liver. Our results suggest that increased parenchymal antigen presentation conferred by hepatocyte CD86 expression prolongs the presence and augments the functions of effector T cells in the liver, thus contributing to HCV-related liver injury.