Myeloid dendritic cells of patients with chronic HCV infection induce proliferation of regulatory T lymphocytes
Department of Medicine, Division of Gastroenterology
Medical Subject Headings
Cell Proliferation; Cytokines; Dendritic Cells; Disease Progression; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Gene Expression; Hepatitis C, Chronic; Humans; Myeloid Cells; RNA; T-Lymphocytes, Regulatory
Gastroenterology | Immunology and Infectious Disease
BACKGROUND and 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.
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Citation: Gastroenterology. 2008 Dec;135(6):2119-27. Epub 2008 Aug 7. Link to article on publisher's site