Myeloid dendritic cells of patients with chronic HCV infection induce proliferation of regulatory T lymphocytes.
OBJECTIVE
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.
University of Massachusetts Medical School, Department of Medicine, Worcester, Massachusetts 01605-2324, USA.
Angela
A
Dolganiuc
Edward
E
Paek
Karen
K
Kodys
Joanne
J
Thomas
Gyongyi
G
Szabo
D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015870:Gene Expression; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D022423:Myeloid Cells / Q000276:immunology* / Q000473:pathology; D012313:RNA / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology*
D016207:Cytokines; D012313:RNA