A first demonstration that type-I IFN may be sensed by Vc9Vd2 Tcells was reported by Kunzmann et al., showing an increase of CD69 after IFN-a treatment. We LY2109761 confirmed this observation and showed the ability of IFN-a to increase Vc9Vd2 T-cell response to PhAgs stimulation in terms of IFN-c production both in HD and in HCV-infected patients. In particular, the significant impairment of Vc9Vd2 T-cells in HCVinfected patients did not allow to obtain their complete restoration by IFN-a. Nevertheless, individual relative impact of PhAg/IFN-a co-stimulation was found much higher in HCV patients, due to the very low level of responsiveness to PhAgs. Thus, the possibility to restore IFN-c production in vivo by combining standard IFN-a treatment and PhAg stimulation may have a positive impact on HCV inhibition. Indeed several reports show that IFN-a and IFNc may synergistically inhibit HCV replication in vitro and this effect is also reported for other viruses. Nevertheless, a study aimed to evaluate the antiviral impact of PhAg/IFN-a combination is ongoing and may validate new combined treatment strategies. Interestingly, PhAg-activated Vc9Vd2 Tcells are able not only to produce IFN-c but also to deploy many different response pathways, such as DC activation, and neutrophils recruitment/activation, thus improving the overall protective immune response capability. Noteworthy, IFNa effect on PhAg/response was found also in vivo in pre-clinical trials on non-human primates, inducing an increase in IFN-c amount in animals sera. A time-course study of in vivo IFN-a treatment on Vc9Vd2 T-cell responsiveness to PhAg in HCVinfected patients is currently in progress. About possible mechanisms mediating this improvement, we found that IFN-a acts by increasing IFN-c-mRNA persistence, that may result in increased IFN-c translation levels. Similar observations were reported on NK cells, as IFN-c production after IL-12 and IL-18 stimulation was regulated by mechanisms involving IFN-c-mRNA stabilization. Indeed, mRNA stabilization is now considered as one of the main post-transcriptional control mechanisms responsible for the initiation and resolution of inflammation. In recent years, a new attention on new direct antiviral drugs for chronic HCV infection is growing. The definition of other combined immunomodulating approaches may contribute to optimize the antiviral response. In this context Vc9Vd2 T-cells may represent a good target of immunomodulating strategies for their ability to be easily activated in vivo by PhAgs without HLA restriction and to orchestrate a complex network of antiviral and immunomodulating activities. We show here for the first time that IFN-a, currently used in standard therapy, is able to improve Vc9Vd2 T-cell responsiveness in HCV patients. This, and the finding that IFN-c can act synergistically with IFN-a to inhibit HCV replication, strengthen the rational for testing combined standard antiviral and immunostimulating therapeutical strategies. To this aim, future in vivo studies on HCV-infected non-human primates aimed to define the antiviral capability of the combined treatment are necessary both to assess safety and antiviral effectiveness of this combined approach, and to disclose the cellular/molecular mechanisms involved. Wnt/b-catenin signalling pathway is critical for early and late embryonic development and it plays important roles during tumorigenesis.