title: Differential dysfunction in dendritic cell subsets during chronic HCV infection.
abstract: Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease with over 200 million individuals infected worldwide. The vast majority of acutely infected humans develop chronic infection, which is characterized by attenuated antiviral T-cell responses. The mechanisms leading to such attenuation/suppression are poorly understood. It has been proposed that dysfunction of antigen-presenting cells (APC) may underlie the downregulation of antiviral immune responses. However, studies using bulk or in vitro-derived APC populations have resulted in conflicting reports. In this study, we evaluated the functional and immunophenotypic features of ex vivo-purified dendritic cell (DC) subsets during chronic HCV infection. We found that plasmacytoid DC (PDC) from HCV-infected patients (HCV-PDC) showed a striking deficit in IFN-alpha production in response to CpG stimulation. In addition, we found that myeloid DC (MDC) from these patients showed a diminished capacity to induce a mixed lymphocyte response (MLR), correlating with lower levels of HLA-DR and CD86 expression and higher IL-10 production in response to poly-IC stimulation. In contrast, HCV-PDC showed increased ability to stimulate an MLR. Of note, within the HCV-PDC preparation, we noted a distinctly expanded DC subset that expressed some markers of MDC, but showed significantly lower HLA-DR and CD86 expression, suggesting an expansion of DC at an immature/intermediate stage of differentiation. Our studies demonstrate distinct and contrasting dysfunctional features in DC subsets and underscore the importance of evaluating APC subpopulations separately.
authors.affiliation: Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Averill
authors.forename: William M
authors.initials: WM
authors.lastname: Lee
authors.forename: Nitin J
authors.initials: NJ
authors.lastname: Karandikar
mesh_terms: D000328:Adult; D017951:Antigen Presentation / Q000276:immunology*; D051940:B7-2 Antigen / Q000096:biosynthesis / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006684:HLA-DR Antigens / Q000096:biosynthesis / Q000276:immunology; D019698:Hepatitis C, Chronic / Q000276:immunology*; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D008875:Middle Aged
chemical_list: D051940:B7-2 Antigen; D006684:HLA-DR Antigens; D016898:Interferon-alpha; D016753:Interleukin-10; D018664:Interleukin-12