15 In this issue of HEPATOLOGY, two selleck compound elegant studies from the laboratories of Jacob Nattermann and Hugo Rosen give important new insights into the biological role of NKp46 in HCV infection.16, 17 Indeed, by using different experimental models and different study cohorts, both studies come to similar conclusions. This itself is a remarkable finding in a field where studies examining the phenotype and function of NK cells have often yielded diverging data. The first important finding of these studies is that high expression of NKp46 (NKp46high) defines a specific human NK-cell subset. Indeed, in comparison to NKp46dim cells, NKp46high

NK cells are characterized by a higher expression of immature differentiation markers, such as CD127, CD62L, and CD27,17 a higher functional ability (e.g., a higher target cell cytotoxicity) and a higher IFN-γ production after stimulation with IL-12 and IL-1516, 17 as well as a stronger up-regulation of genes involved in cytotoxicicty after stimulation with Toll-like receptor ligands.16 Although the majority of the NKp46high NK-cell subset is also CD56bright, differences in functional

and phenotypical properties indicate that NKp46 expression defines a unique NK-cell subset. buy Selumetinib This is further supported by microarray analysis that showed a differential regulation of more than 800 genes in NKp46high versus CD56bright NK cells.17 Importantly, by using NK cells from chronically HCV-infected patients17 or from healthy donors16 and by using the replicon system17 or the Huh7.5 Japanese fulmanant hepatitis type 1 in vitro infection system16 as a readout, both studies show that NKp46high cells have an

increased anti-HCV activity. Most likely, combined noncytolytic and cytolytic effector functions contribute to the antiviral activity of NKp46high NK cells. Indeed, Krämer et al. provide evidence that soluble factors, specifically IFN-γ, contribute to the antiviral effect, Branched chain aminotransferase because incubation of HCV-replicating Huh7 cells with supernatants from NKp46high cells led to a significant inhibition of HCV replication and because this inhibition could be effectively blocked by the addition of anti-IFN-γ.17 This is in agreement with previous studies that have shown a control of HCV replication by NK-cell IFN-γ secretion in vitro18, 19 and after adoptive transfer of NK/NK T cells after liver transplantation in vivo.20 The contribution of cytolytic effector mechanisms in NKp46-mediated antiviral activity is supported by studies showing that cytotoxicity is the major mechanism involved in NK-cell-mediated elimination of HCV-infected hepatocytes21 and that NK cells can kill HCV-infected hepatocytes by perforin/granzyme and TNF-related apoptosis-inducing ligand–mediated mechanisms.