IFN-α and-β)–modulated upregulation of cellular genes that are key mediators of antiviral defenses. Cellular proteins such as RNA helicase retinoic acid–inducible gene I (RIG-I) and Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns, which are the hallmark of viral infections (1, 2). Consequently, many viruses have developed strategies to evade the IFN system. Hepatitis C virus (HCV), a livertropic virus that chronically infects approximately 170 million people worldwide (3), is able to attenuate the IFN response at multiple levels within infected hepatocytes. For example, viral NS3/4A protease is able to cleave key intermediate proteins that are involved in TLR3-and RIG-I–mediated antiviral signaling (Fig. 1) in cultured cells (reviewed in ref. 4). Furthermore, viral NS5A protein is able to block activation of the double-stranded RNA–activated protein kinase PKR (reviewed in ref 4). Curiously, HCV infection induces a robust production of IFN-stimulated genes in the liver (5, 6). These observations present a conundrum: HCV inhibits production of IFN and IFN-stimulated genes (ISGs) in the cultured liver, yet induces IFN production in the infected organ. Either the virus cannot block IFN-mediated antiviral responses in the highly differentiated liver organ, or IFN is produced in the liver by cells other than HCV-infected hepatocytes.

Takahashi et al.(7) provide evidence that IFN is produced from a highly specialized class of dendritic cells known as plasmacytoid dendritic cells (pDCs) that are known to infiltrate the liver during HCV infection (Fig. 1). The authors showed that cocultivation of human pDCs purified from peripheral blood mononuclear cells (PBMCs) with HCV-infected hepatocytes resulted in marked IFN production that was proportional to the number of HCV-infected cells (7). Total PBMCs, but not pDC-depleted PBMCs, produced IFN when cocultured with HCV-infected hepatocytes, arguing that the pDCs themselves were the sources of IFN. Curiously, only approximately 10% of the pDCs in coculture produced IFN (7). This finding suggests that only a subpopulation of pDCs can be activated, or that activation of pDCs requires a limiting