Myeloid Dendritic Cells of Patients With Chronic HCV Infection Induce Proliferation of Regulatory T Lymphocytes

Abstract

Background & Aims: Dendritic cells (DCs) initiate and sustain an efficient T-lymphocyte response. Chronic hepatitis C virus (HCV) infection is associated with inefficient T-cell functions that fail to eradicate the virus, so defects in DC function might be involved in HCV pathogenesis. This study analyzed the activities of myeloid DCs and distinct CD4+ T-cell populations in samples collected from patients with HCV. Methods: The abilities of primary BDCA1+ or monocyte-derived DCs from HCV patients (HCV-DC) to stimulate CD4+, CD4+CD25-, or different ratios of CD4+CD25+/CD4+CD25- T cells were evaluated in mixed lymphocyte reactions. T-cell proliferation and phenotype were evaluated by flow cytometry; cytokine production was evaluated by enzyme-linked immunosorbent assay and marker expression by polymerase chain reaction analyses. Results: HCV-DCs were poor activators of CD4+ T cells; this defect was reversed by addition of interleukin-2, neutralization of interleukin-10, or elimination of CD4+CD25+ T cells. HCV-DC stimulated proliferation of regulatory T cells (Tregs; CD4+CD25+FoxP3+), which limit proliferation of HCV-specific T lymphocytes. We observed an increased frequency of CD4+CD25+ T cells in peripheral blood of HCV patients and that HCV-DC overexpressed a number of alternative costimulatory molecules, including PD-L1. Finally, HCV-DC stimulated expansion rather than de novo induction of FoxP3+ Tregs. Conclusions: Our results indicate a role for myeloid DC in expansion of Tregs to promote chronic infection of patients with HCV. © 2008 AGA Institute.