Accumulation of Intrahepatic TNF-α-Producing NKp44(+) NK Cells Correlates With Liver Fibrosis and Viral Load in Chronic HCV Infection

In the setting of chronic hepatitis C virus (HCV) infection, changes in natural killer (NK) cells have been shown to reflect activation in response to virus stimulation. The contribution of individual natural cytotoxicity receptors to HCV infection remains to be clarified. NKp44 is the sole specific natural cytotoxicity receptor expressed only on activated NK cells. In this study, peripheral blood and liver NK-cell subsets were purified from 31 patients with chronic C hepatitis or nonalcoholic steatohepatitis, and then characterized by flow cytometry. Their polyfunctional activity was determined by expression of the CD107a degranulation marker, together with intracellular cytokine production. Unlike the patients with nonalcoholic steatohepatitis, patients with chronic HCV infection had a higher frequency of NKp44(+) NK cells in the liver than in their peripheral blood (P < 0.0001). Intrahepatic NKp44(+) NK cells from HCV(+) individuals produced higher levels of tumor necrosis factor-α than did NKp44(−) NK cells (P = 0.0011). Importantly, the frequency of intrahepatic NKp44(+) NK cells was correlated with both HCV-RNA levels (P = 0.0234) and stage of fibrosis (P = 0.0003). Our findings suggest that the accumulation of intrahepatic tumor necrosis factor-α-producing NKp44(+) resident NK cells play a role in the liver damage associated with chronic HCV infection.