Pathogenesis of chronic viral hepatitis: differential roles of T cells and NK cells

Abstract

Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections account for 57% of cases of liver cirrhosis and 78% of cases of primary liver cancer worldwide and cause a million deaths per year. Although HBV and HCV differ in their genome structures, replication strategies and life cycles, they have common features, including their noncytopathic nature and their capacity to induce chronic liver disease, which is thought to be immune mediated. However, the rate of disease progression from chronic hepatitis to cirrhosis varies greatly among infected individuals, and the factors that regulate it are largely unknown. This review summarizes our current understanding of the roles of antigen-specific and nonspecific immune cells in the pathogenesis of chronic hepatitis B and C and discusses recent findings that identify natural killer cells as regulators of T cell function and liver inflammation.

Fig. 1. Natural history of chronic HBV and HCV infections

A. Most chronic HBV infections result from vertical transmission from infected mother to neonate or young infant. B. Most chronic HCV infections result from horizontal transmission during adulthood. Whereas patients with chronic HBV infection experience multiple phases with distinct viremia and pathology patterns, these parameters tend to be less pronounced and more stable in chronic HCV infection (see text for details).

Fig. 2

Pathogenesis of HBV-related liver disease. Simplified schematic presentation of key factors that contribute to the pathogenesis of acute and chronic liver disease. As described in box 3 these findings are mostly based on observations made in transgenic mice that express HBsAg or replicate the complete HBV genome in their hepatocytes and were reconstituted with HBs-specific CD8 T cells ^,,–.

Fig. 3

NK cell-mediated lysis of intrahepatic cells involved in the pathogenesis of viral hepatitis. As described in detail in the main text, the drawing integrates results from the LCMV-model of viral hepatitis and from translational studies with biospecimens from HBV and HCV infected patients. Chronic exposure to IFN-α induces increased STAT1 levels and preferential STAT1 over STAT4 phosphorylation ^, resulting in increased cytotoxicity rather than IFN-γ production in HCV-infected patients ^, and LCMV-infected mice ^,. In HBV infection, increased NK cell cytotoxicity has been attributed to IL-10 and TGF-β exposure . (1) NK cells kill activated CD4 T cells in a perforin-dependent manner, which results in reduced CD4 help to CD8 T cells and exhaustion of the LCMV-specific T cell response after high dose LCMV infection . (2) Additional mechanisms of CD8 T cell regulation include perforin-mediated lysis of activated CD8 T cells that upregulate NKG2D in response to IL-10 in the LCMV model ^,, and TRAIL-mediated lysis of activated CD8 T cells that express TRAIL-R2 in HBV infection . CD8 T cells can upregulate CD48 to engage the inhibitory NK cell receptor CD244 (2B4) as a negative feedback mechanism. (3) NK cells also lyse human hepatocytes in HBV infection as well as (4) activated human and mouse stellate cells with altered expression of activatory and inhibitory NK cell ligands.

Fig. 4. NK cell-mediated regulation of antiviral T cell responses as observed in the LCMV model of viral hepatitis

A. The differential effect of NK cells on viremia and pathology depends on the size of the LCMV inoculum and is associated with differential T cell response patterns . B. NK cells serve as rheostats of disease activity (see text for details).