NK cells: a double-edged sword in chronic hepatitis B virus infection

Abstract

There is natural enrichment of NK cells in the human liver and this intrahepatic predominance underscores their potential importance in the control of infections with hepatotropic viruses such as hepatitis B virus (HBV). The contribution of innate components during chronic HBV infection has been a relatively under-investigated area. However, recent data have highlighted that NK cells are capable of exerting antiviral and immunoregulatory functions whilst also contributing to the pathogenesis of liver injury via death receptor pathways. We will present an overview of current knowledge regarding the complex biology of NK cells in the context of their antiviral versus pathogenic role in chronic hepatitis B as a clinically relevant avenue for further investigation.

Keywords: CD56bright; IFN-alfa; IL-10; NK cells; TRAIL; hepatitis B virus; interferon-gamma; liver damage.

Figure 1

(A) Potential influences of the hepatic milieu on NK cells. The liver sinusoidal endothelial network is extensive and narrow, with sluggish blood flow encouraging intimate contact between circulating and resident cell types. NK cells are exposed to a milieu rich in IL-10 and TGF-β and can interact with ligands on a number of specialized resident liver cells such as galectin-9 on Kupffer cells and NKG2D on hepatocytes. They may also be influenced by inhibitory/stimulatory ligands expressed by liver sinusoidal endothelial cells or stellate cells. (B) Functions of NK cells in the HBV-infected liver. NK cells can utilize death ligands to kill hepatocytes (contributing to liver damage) and HBV-specific T cells (curtailing antiviral immunity). They exhibit impaired non-cytolytic antiviral function (reduced IFN-γ production), but may serve a protective function to limit liver fibrosis by killing activated stellate (pro-fibrotic) cells.