Hepatic enrichment and activation of myeloid dendritic cells during chronic hepatitis C virus infection

• Type of Material: Article
• Authors: Victoria M. Velazquez, Emory University; Huiming Hon, Emory University; Chris Ibegbu, Emory University; Stuart J Knechtle, Emory University; Allan D Kirk, Emory University; Arash Grakoui, Emory University
• Language: English
• Date: 2012-12
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 American Association for the Study of Liver Diseases
• Final Published Version (URL): http://onlinelibrary.wiley.com/doi/10.1002/hep.25904/abstract
• Title of Journal or Parent Work: Hepatology
• ISSN: 0270-9139
• Volume: 56
• Issue: 6
• Start Page: 2071
• End Page: 2081
• Grant/Funding Information: This study was supported in part from the National Research Service Award Institutional Research Training Grants T32 AI007470, T32 AI007610, and American Liver Foundation (VMV); EVC/CFAR Immunology Core P30 AI050409 (CI, AG); Yerkes Research Center Base Grant RR-00165, and Public Health Service DK083356 and AI070101 (AG).
• Keywords: myeloid DC; inhibitory molecules; antiviral immunity; liver; transplantation; cross presentation; plasmacytoid DC; antigen presentation
• Research Categories: Health Sciences, Immunology; Health Sciences, Medicine and Surgery

Abstract

Chronic hepatitis C virus (HCV) infection is a serious disease that can result in numerous long-term complications leading to liver failure or death. Approximately 80% of people fail to clear their infection, largely as the result of weak, narrowly targeting or waning antiviral T cell responses. While professional antigen presenting cells (APCs) like dendritic cells (DCs) might serve as targets for modulation of T cell immunity, the particular role of DCs in immunity to HCV is not known. Moreover the identity, phenotype and functional characteristics of such populations in the liver, the site of HCV replication, have proven difficult to elucidate. Using a multicolor flow-based approach, we identified six distinct populations of professional APCs among liver interstitial leukocytes isolated from uninfected and HCV-infected patients. While a generalized enrichment of DCs in the liver compared to blood was observed for all patients, HCV infection was characterized by a significant increase in the frequency of intrahepatic myeloid DCs (both CD1c+ and CD141+). Phenotypic analyses of liver plasmacytoid (pDC) and myeloid DCs (mDC) further revealed the HCV-induced expression of maturation molecules CD80, CD83, CD40 and PD-L1. Importantly pDC and mDCs from HCV-infected liver were capable of secreting effector cytokines, IFN-α and IL-12 respectively, in response to TLR stimulation in vitro.Conclusion Chronic HCV infection facilitates the “customized” recruitment of liver DC subsets with established functional roles in antigen presentation. These DCs are characterized by a mature, activated phenotype and are functionally responsive to antigenic stimulation in vitro. Such findings highlight an important paradox surrounding liver DC recruitment during HCV infection, where despite their activation these cells do not provide adequate protection from the virus.