This study was conducted to examine the interactions among the innate and adaptive immune components of the liver parenchyma during acute viral hepatitis. Mice were i.v. infected with a recombinant adenovirus, and within the first 24 h of infection, we found a transient, but significant, accumulation of IL-17 and IL-23 in the liver. In vivo neutralization of these interleukins alleviated the liver injury. Further investigations showed that IL-17 neutralization halted the intrahepatic accumulation of CTL and Th1 cells. A majority of the IL-17-producing cells in the liver were γδ T cells. Additionally, intrahepatic IL-17+ γδ T cells, but not the IFN-γ+ ones, preferentially expressed IL-7Rα (CD127) on their surface, which coincided with an elevation of hepatocyte-derived IL-7 at 12 h post-infection. IL-7Rα blockade in vivo severely impeded the expansion of IL-17-producing cells following viral infection. In vitro, IL-7 synergized with IL-23 and directly stimulated IL-17 production from γδ T cells in response to TCRγδ stimulation. Finally, type I interferon (IFN-I) signaling was found to be critical for hepatic IL-7 induction. Collectively, these results showed that the IFN-I/IL-7/IL-17 cascade was important in priming T cell responses in the liver. Moreover, the highly coordinated cross talk among hepatocytes and innate and adaptive immune cells played a critical role in antiviral immunity in hepatitis.

The TT virus (TTV) is a non-enveloped, single-stranded, circular, DNA virus, first isolated from a patient with hepatitis of unexplained etiology. The much deliberated pathological role of the virus continues to be conjectural in the absence of a suitable in vitro replication model. So far, the liver and the bone marrow have been shown to be the main sites of TTV replication. In this study, the human cell lines HepG2 and Chang Liver, the rat hepatoma cell line MH1C1, phytohemagglutinin (PHA)-stimulated TTV-negative peripheral blood mononuclear cell (PBMC) cultures and the B lymphoblast cell line, Raji were investigated as potential in vitro replication systems for TTV. The cell lines were infected with an inoculum prepared by pooling TTV genotype1 DNA positive sera and monitored for virus replication. Of the three hepatocyte cell lines, while the HepG2 and MH1C1 cell lines did not support TTV replication, the Chang Liver cell line showed clear morphological changes as a result of the in vitro infection, which included clumping and granular degeneration of the entire cell sheet over a period of 6 days. The infected cells also showed presence of virus-specific mRNA representative of viral transcription. The consistent presence of infectious viral particles in the supernatant culture fluid at 24-hr fluid replacement intervals indicated limited extra-cellular release of viral particles. The PHA-stimulated TTV-negative PBMC cultures and the Raji cell line were also able to support TTV replication and released significant levels of infectious viral particles into the supernantant culture fluid.

The autophagy pathway represents an evolutionarily conserved cell recycling process that is activated in response to nutrient deprivation and other stress signals. Over the years, it has been linked to an array of cellular functions. Equally, a wide range of cell-intrinsic, as well as extracellular, factors have been implicated in the induction of the autophagy pathway. Microbial infections represent one such factor that can not only activate autophagy through specific mechanisms but also manipulate the response to the invading microbe’s advantage. Moreover, in many cases, particularly among viruses, the pathway has been shown to be intricately involved in the replication cycle of the pathogen. Conversely, autophagy also plays a role in combating the infection process, both through direct destruction of the pathogen and as one of the key mediating factors in the host defense mechanisms of innate and adaptive immunity. Further, the pathway also plays a role in controlling the pathogenesis of infectious diseases by regulating inflammation. In this review, we discuss various interactions between pathogens and the cellular autophagic response and summarize the immunological functions of the autophagy pathway.

BACKGROUND & AIMS The hepatitis C virus (HCV) serine protease NS3/4A can cleave mitochondria-associated, anti-viral signaling protein (MAVS) and block retinoic acid-inducible gene I–mediated interferon (IFN) responses. Although this mechanism is thought to have an important role in HCV-mediated innate immunosuppression, its significance in viral persistence is not clear. METHODS We generated transgenic mice that express the HCV NS3/4A proteins specifically in the liver and challenged the animals with a recombinant vesicular stomatitis virus (VSV), a synthetic HCV genome, IFN-α, or IFN-β. We evaluated the effects of HCV serine protease on the innate immune responses and their interactions. RESULTS Expression of HCV NS3/4A resulted in cleavage of intrahepatic MAVS; challenge of transgenic mice with VSV or a synthetic HCV genome induced strong, type I IFN-mediated responses that were not significantly lower than those of control mice. Different challenge agents induced production of different ratios of IFN-α and -β, resulting in different autophagic responses and vesicular trafficking patterns of endoplasmic reticulum- and mitochondria-associated viral proteins. IFN-β promoted degradation of the viral proteins by the autolysosome. Variant isoforms of MAVS were associated with distinct, type I IFN-mediated autophagic responses; these responses have a role in trafficking of viral components to endosomal compartments that contain toll-like receptor -3. CONCLUSIONS IFN-β-mediates a distinct autophagic mechanism of anti-viral host defense. MAVS have an important role in type I IFN-induced autophagic trafficking of viral proteins.

Type 1 interferon (IFN-I) promotes antigen-presenting cell maturation and was recently shown to induce hepatic IL-7 production during infection. Herein, we further explored the underlying mechanisms used by IFN-I to orchestrate antiviral immune responses in the liver. Acute viral hepatitis was induced by i.v. injection of adenovirus (Ad) in IFN-a receptor knockout (IFNAR 2/2 ) and control mice. To disrupt signaling, monoclonal antibodies (mAbs) against IL-7 receptor alpha (IL-7Ra) or PD-L1 were i.p. injected. We found that CD8 1 T cells in IFNAR 2/2 mice were less effective than those in control mice. The reduced T-cell function was accompanied by increased levels of PD-1 expression, apoptosis and decreased IFN-c production. The lack of IFN-I signaling also impaired the expression of accessory molecules in both intrahepatic dendritic cell (DCs) and hepatocytes. PD-L1 was comparably and highly expressed on hepatocytes in both IFNAR 2/2 and control mice. Injection of PD-L1-specific mAb in IFNAR 2/2 mice reversed the compromised immune responses in the liver. Further investigation showed that hepatic IL-7 elevation was less pronounced in IFNAR 2/2 mice compared to the controls. A treatment with recombinant IL-7 suppressed PD-1 expression on CD8 1 T cells in vitro. Accordingly, blocking IL-7R signaling in vivo resulted in increased PD-1 expression on CD8 1 T cells in Ad-infected mice. Collectively, the results suggest that IFN-I-induced hepatic IL-7 production maintains antiviral CD8 1 T-cell responses and homeostasis by suppressing PD-1 expression in acute viral hepatitis.