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Functional Behavior of NKp46-Positive Intrahepatic Natural Killer Cells Against Hepatitis C Virus Reinfection After Liver Transplantation

Background NKp46 expression in natural killer (NK) cells has recently been shown to affect the responsiveness to antiviral treatment in hepatitis C virus (HCV)-infected patients. However, the density of NKp46 on intrahepatic NK cells is remarkably higher than that on peripherally circulating NK cells, whereas the biophylactic function of intrahepatic NK cells against HCV reinfection remains unclear. Methods We analyzed the phenotypic and functional properties of intrahepatic NK cells using mononuclear cells extracted from ex vivo liver perfusates from living liver transplantation donors. To investigate the role of intrahepatic NK cells in relation to HCV infection, we evaluated posttransplant HCV load kinetics in HCV-related patients. Results Intrahepatic NK cells from healthy donors showed a distinctive phenotype even in each of the CD56bright and CD56dim fractions compared with peripheral blood NK cells. In the assays using a Huh7-HCV replicon system, anti-HCV activity was induced via recognition of the NK cell receptors, including NKp46, NKp30, and NKG2D, which was demonstrated by the use of monoclonal antibodies that neutralized neutralizing molecules. Unexpectedly, the density of NKp46 on intrahepatic NK cells varied considerably among individuals, allowing us to demonstrate that HCV reload in the early posttransplant period was delayed in recipients of liver allografts containing a higher proportion of NKp46high NK cells. Conclusions Intrahepatic NKp46high NK cells exhibited anti-HCV activity via cell-to-cell contact. The variation of the NKp46high proportion in individuals could be attributed to the diversity of HCV resistance observed in these individuals, which possibly reflects the clinical outcome of infection in patients.