Natural Killer Cells in Viral Hepatitis

Abstract

Natural killer (NK) cells are traditionally regarded as first-line effectors of the innate immune response, but they also have a distinct role in chronic infection. Here, we review the role of NK cells against hepatitis C virus (HCV) and hepatitis B virus (HBV), two agents that cause acute and chronic hepatitis in humans. Interest in NK cells was initially sparked by genetic studies that demonstrated an association between NK cell-related genes and the outcome of HCV infection. Viral hepatitis also provides a model to study the NK cell response to both endogenous and exogenous type I interferon (IFN). Levels of IFN-stimulated genes increase in both acute and chronic HCV infection and pegylated IFNα has been the mainstay of HCV and HBV treatment for decades. In chronic viral hepatitis, NK cells display decreased production of antiviral cytokines. This phenotype is found in both HCV and HBV infection but is induced by different mechanisms. Potent antivirals now provide the opportunity to study the reversibility of the suppressed cytokine production of NK cells in comparison with the antigen-induced defect in IFNγ and tumor necrosis factor-α production of virus-specific T cells. This has implications for immune reconstitution in other conditions of chronic inflammation and immune exhaustion, such as human immunodeficiency virus infection and cancer.

Keywords: HBV; HCV; Infection; Interferon; T Cell.

Figure 1

Altered natural killer (NK) cell function in chronic hepatitis C virus (HCV) infection. NK cells are activated in HCV infection with greater signaling from activating than inhibitory receptors (see text for details). Polarization of NK cell function toward increased (solid line) cytotoxicity and decreased (dotted line) production of antiviral cytokines, , is driven by type I interferon (IFN), produced by Toll-like receptor 7 (TLR7)-stimulated plasmacytoid dendritic cells, and other nonparenchymal cells (not pictured). Mechanisms mediated by interleukin-10 (IL-10), which contribute to this NK cell phenotype in hepatitis B virus (HBV) infection, may also be operative in HCV infection because virus-specific T cells that secrete IL-10 have been demonstrated in the liver. IL-10 is also directly induced in NK cells via interaction of the inhibitory NKG2A/CD94 receptor with human leukocyte antigen E (HLA-E) on HCV-infected hepatocytes. HLA-E is thought to be stabilized by an endogenously processed HCVcore peptide and therefore expressed at increased levels. Suboptimal production (dotted line) of IL-18 and IL-2 may further decrease IFNγ production by NK cells. Monocytes from patients with chronic HCV infection produce less IL-18 than monocytes from healthy controls upon coculture with HCV-replicating hepatocytes and NK cells. HCV-specific CD4 T-cell responses and IL-2 production are reduced in HCV infection.

Figure 2

Altered natural killer (NK) cell function in chronic hepatitis B virus (HBV) infection. Activated NK cells display a similar functional phenotype of increased cytotoxicity (increased tumor necrosis factor-related apoptosis-inducing ligand [TRAIL] production, conserved cytotoxicity) and decreased cytokine production in HBV infection as seen in chronic hepatitis C virus (HCV) infection, but it appears to be induced by transforming growth factor β (TGFβ) and interleukin-10 (IL-10) rather than by type I interferon (IFN). Neutralization of TGFβ and IL-10 normalizes NK cell function in vitro. IL-10–producing regulatory B cells have been described in HBV infection and may contribute to the phenotype. In contrast to HCV infection, increased interferon-stimulated gene (ISG) levels are not a typical feature of chronic HBV infection.