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IFN-λ inhibits HCV replication and triggers IFN-dependent genes. We hypothesized that IFN-λ is immunomodulatory and evaluated its effects on myeloid dendritic cells (DC). DCs generated with IFN-λ (IFN-λ-DC) expressed normal levels of DC markers, but showed reduced allostimulatory capacity in mixed lymphocyte reaction (MLR), similar to DCs of patients with chronic HCV infection (HCV-DC). No additive effects of IFN-λ subtypes were observed. The inhibition of MLR was due to preferential expansion of CD4+CD25+ T cells in the presence of HCV-DCs or IFN-λ-DC, but not normal DCs. Purified CD4+CD25+ T cells from MLR were Foxp3+, CD45RA+, produced IL-10 and TGFb, and inhibited CD4+CD25− T cell proliferation. HCV-DCs produced increased levels of IFN-λ compared to controls. In vitro generation of DCs in the presence of LPS increased expression of IFN-λ. Interestingly, we found increased plasma levels of LPS in HCV patients compared to controls suggesting a possible in vivo mechanism for IFN-λ induction. Further, in vitro DCs generation with LPS resulted in expansion of Tregs and inhibition of MLR, thus mimicking the effects of HCV-DCs and IFN-λ-DCs. We also identified an increased frequency of Tregs in peripheral blood of HCV patients (12±2%) compared to controls (5±1%) (p