Natural killer cells in viral hepatitis: facts and controversies

Abstract

Hepatitis B virus (HBV) and hepatitis C virus (HCV) are major human hepatotropic pathogens responsible for a large number of chronic infections worldwide. Their persistence is thought to result from inefficiencies of innate and adaptive immune responses; however, very little information is available on the former. Natural killer (NK) cells are a major component of innate immunity and their activity is tightly regulated by several inhibitory and activating receptors. In this review, we examine controversial findings regarding the role of NK cells in the pathogenesis of acute and chronic liver disease caused by HCV and HBV. Recent studies built up on technical advances to identify NK receptors and their functional correlates in this setting. While NK cells seem to behave correctly during acute hepatitis, it would appear that the NK cytotoxic potential is generally conserved in chronic hepatitis, if not increased in the case of HCV. In contrast, their ability to secrete antiviral cytokines such as interferon ex vivo or after cytokine stimulation is severely impaired. Current evidence suggests the existence of an NK cell functional dichotomy, which may contribute to virus persistence, while maintaining low-level chronic liver inflammation. The study of liver-infiltrating NK cells is still at the very beginning, but it is likely that it will shed more light on the role of this simple and at the same time complex innate immune cell in liver disease.