Hepatitis C virus (HCV) establishes chronic infection in the liver of nearly 80% of those infected and in addition to causing hepatitis, may cause liver cirrhosis and hepatocellular carcinoma. These detrimental long-term sequelae of persistent HCV infection now comprise the leading indication for liver transplantation in the United States. Defining the elements of the immune response that fail or are insufficient to mediate HCV clearance or resolution in the majority of those infected is critical for advancing our understanding of how to therapeutically intervene in HCV disease pathogenesis. It is known in murine models that a subset of liver dendritic cells, pDCs, express the co-inhibitory molecule B7-H1 to mediate PD-1 dependent T cell dysfunction and that another subset, the mDCs, are capable of inhibiting T cell proliferation and inducing T cell apoptosis. Therefore we hypothesized that defects in DC function might contribute to the establishment of chronic HCV infection. In looking at DC populations in HCV-infected liver we observed: (i) a marked absence of a novel population of myeloid DC progenitors, (ii) an influx of mature DCs compared to uninfected liver and (iii) an activated DC population expressing high levels of T cell co-stimulatory and co-inhibitory molecules. Based on these data we now hypothesize that the chronic HCV liver microenvironment promotes the differentiation of myeloid liver DCs, and that these DCs skew HCV-specific T cell responses toward the induction of tolerance through B7-mediated inhibition and aberrant cytokine secretion. We now propose to study the effects of HCV infection on liver DC recruitment and activation and to test the capacity of liver DC subsets from chronically infected patients to process and present HCV-derived antigens to CD4+ and CD8+ T cells. These studies will identify potential defects in the functional DC response to HCV-infection, and will reveal potential targets for therapeutic intervention.
Hepatitis C virus (HCV) infection is a major global health problem;there are currently 2.5 million Americans chronically infected with HCV and this number increases to a staggering 170 million worldwide. A significant number of these individuals will go on to develop severe complications including liver cirrhosis and hepatocellular carcinoma. We are seeking to understand the mechanisms by which host immune response fails in the majority of those infected and reveal potential targets for therapeutic intervention.
|Tedesco, Dana; Thapa, Manoj; Chin, Chui Yoke et al. (2018) Alterations in Intestinal Microbiota Lead to Production of Interleukin 17 by Intrahepatic ?? T-Cell Receptor-Positive Cells and Pathogenesis of Cholestatic Liver Disease. Gastroenterology 154:2178-2193|
|Tedesco, Dana; Grakoui, Arash (2018) Environmental peer pressure: CD4+ T cell help in tolerance and transplantation. Liver Transpl 24:89-97|
|Aguilar-Valenzuela, Renan; Netland, Jason; Seo, Young-Jin et al. (2018) Dynamics of Tissue-Specific CD8+ T Cell Responses during West Nile Virus Infection. J Virol 92:|
|Tedesco, Dana; Thapa, Manoj; Gumber, Sanjeev et al. (2017) CD4+ Foxp3+ T cells promote aberrant immunoglobulin G production and maintain CD8+ T-cell suppression during chronic liver disease. Hepatology 65:661-677|
|Boisvert, Maude; Zhang, Wanrui; Elrod, Elizabeth J et al. (2016) Novel E2 Glycoprotein Tetramer Detects Hepatitis C Virus-Specific Memory B Cells. J Immunol 197:4848-4858|
|Grakoui, Arash; Crispe, Ian Nicholas (2016) Presentation of hepatocellular antigens. Cell Mol Immunol 13:293-300|
|Price, Aryn A; Grakoui, Arash; Weiss, David S (2016) Harnessing the Prokaryotic Adaptive Immune System as a Eukaryotic Antiviral Defense. Trends Microbiol 24:294-306|
|Honegger, Jonathan R; Tedesco, Dana; Kohout, Jennifer A et al. (2016) Influence of IFNL3 and HLA-DPB1 genotype on postpartum control of hepatitis C virus replication and T-cell recovery. Proc Natl Acad Sci U S A 113:10684-9|
|Price, Aryn A; Tedesco, Dana; Prasad, Mona R et al. (2016) Prolonged activation of innate antiviral gene signature after childbirth is determined by IFNL3 genotype. Proc Natl Acad Sci U S A 113:10678-83|
|Moradpour, Darius; Grakoui, Arash; Manns, Michael P (2016) Future landscape of hepatitis C research - Basic, translational and clinical perspectives. J Hepatol 65:S143-S155|
Showing the most recent 10 out of 41 publications