Indeed, reduced NKp30 levels have been observed on NK cells from HCV patients[6]. NK cells. We conclude that NKG2D-dependent NK cell functions are modulated during chronic HCV infection, and demonstrate that this alteration can be prevented by exogenous IL-15, which could represent a meaningful adjuvant for therapeutic intervention. == Author Summary == Natural killer (NK) cells are part of the innate immune response against virus infection. Their activation is the net result of signals emanating from a panel of inhibitory and activating receptors, among which the NKG2D activating receptor plays a major role. NKG2D ligands, the MHC class I related Chain (MIC) molecules, are induced on HCV-infected hepatocytes. In this paper, we show that NKG2D expression is decreased on NK cells from chronically infected HCV patients. As a consequence, NK cell cytolytic and IFN-producing functions are impaired. We show that this phenomenon is mediated by TGF produced by monocytes upon stimulation by the non-structural HCV-NS5A protein. NS5A could bind to TLR4 on monocytes, thus inducing the production of IL-10 and TGF, while inhibiting the production of IL-12. We further showed that TLR4-dependent IL-10 production by monocytes upon NS5A stimulation was mediated through the p38 and PI3 kinase DJ-V-159 pathways. In addition, we demonstrated that IL-15 could inhibit the TGF-mediated effects on NKG2D expression and NK cell functions. Collectively, these results identify a new dampening signal used by HCV to subvert innate immune response, and may provide new insights into the design of new strategies to restore NK cell functions in chronic hepatitis C. == Introduction == Natural Killer (NK) cells are effectors of the rapidly acting antiviral innate immune system. They kill virally infected cells and DJ-V-159 are an important source of antiviral cytokines such as IFN. In addition, they establish an early and efficient dialogue with professional antigen presenting cells (APCs) that in turn, orchestrate the adaptive immune response towards Th1-type antiviral immunity[1]. NK cell activation is tightly regulated by the integration of signals emanating from a diverse array of inhibitory and activating receptors[2]. Inhibitory receptors, including Killer cell Immunoglobulin-like receptors (KIRs) and CD94/NKG2A, gauge expression of MHC class I molecules which can be compromised by viral immune subversion, and thus serves as an indicator of the integrity of cells. Activating receptors, including the natural cytotoxicity receptors (NCRs) and NKG2D, usually detect the presence of infectious non-self and/or stress-induced self ligands at the surface of infected cells. Hepatitis C virus (HCV), which replicates in hepatocytes, mediates a chronic liver infection in the majority of infected individuals. NK cells abound in the normal liver, where they make up to 30% of resident hepatic lymphocytes[3]. This huge amount of NK cells in the liver suggests that they are important sentinel cells, surveying the liver for signs of damage or Slc7a7 cellular stress. However, it also implies that HCV must divert NK cell-mediated responses in order to establish persistent infection. The importance of NK cells in the resolution of HCV infection is illustrated by the influence of genetic polymorphisms of KIR and their HLA ligands on the outcome of HCV infection[4]. Various alterations of NK cell phenotype have been described during chronic DJ-V-159 HCV infection, but results are often contradictory regarding the experimental conditions used (ex vivo or in vitro cytokine-stimulated), the modifications involved and their consequences on effector functions[5],[6],[7],[8],[9],[10],[11]. The NKG2D activating receptor is constitutively expressed on human NK and CD8 T cells[12]. Its ligands, the MHC class I chain-related A and B proteins (MICA and MICB) and UL-16 binding proteins (ULBP14), are almost undetectable in normal tissues, but are induced on the cell surface by various stresses such as DNA damage, tumor transformation and intracellular infection. The importance of the NKG2D defense system is highlighted by the observation that tumors and viruses have developed several mechanisms for evading NKG2D-mediated recognition[13],[14],[15],[16],[17]. The overall contribution of the NKG2D pathway in the control of HCV infection is unclear[7],[10]. We show here that NKG2D is downmodulated on circulating NK cells, and consequently NK cells are functionally impaired. This defect is mediated by the HCV-NS5A protein, which disturbs.