title: Regulatory T cells suppress in vitro proliferation of virus-specific CD8+ T cells during persistent hepatitis C virus infection.
abstract: The basis of chronic infection following exposure to hepatitis C virus (HCV) infection is unexplained. One factor may be the low frequency and immature phenotype of virus-specific CD8(+) T cells. The role of CD4(+)CD25(+) T regulatory (T(reg)) cells in priming and expanding virus-specific CD8(+) T cells was investigated. Twenty HLA-A2-positive patients with persistent HCV infection and 46 healthy controls were studied. Virus-specific CD8(+) T-cell proliferation and gamma interferon (IFN-gamma) frequency were analyzed with/without depletion of T(reg) cells, using peptides derived from HCV, Epstein-Barr virus (EBV), and cytomegalovirus (CMV). CD4(+)CD25(+) T(reg) cells inhibited anti-CD3/CD28 CD8(+) T-cell proliferation and perforin expression. Depletion of CD4(+)CD25(+) T(reg) cells from chronic HCV patients in vitro increased HCV and EBV peptide-driven expansion (P = 0.0005 and P = 0.002, respectively) and also the number of HCV- and EBV-specific IFN-gamma-expressing CD8(+) T cells. Although stimulated CD8(+) T cells expressed receptors for transforming growth factor beta and interleukin-10, the presence of antibody to transforming growth factor beta and interleukin-10 had no effect on the suppressive effect of CD4(+)CD25(+) regulatory T cells on CD8(+) T-cell proliferation. In conclusion, marked CD4(+)CD25(+) regulatory T-cell activity is present in patients with chronic HCV infection, which may contribute to weak HCV-specific CD8(+) T-cell responses and viral persistence.
authors.affiliation: Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford, South Parks Road, Oxford OX1 3SY, United Kingdom.
authors.forename: Simon M
authors.initials: SM
authors.lastname: Rushbrook
authors.forename: Scott M
authors.initials: SM
authors.lastname: Ward
authors.forename: Esther
authors.initials: E
authors.lastname: Unitt
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Vowler
authors.forename: Michaela
authors.initials: M
authors.lastname: Lucas
authors.forename: Paul
authors.initials: P
authors.lastname: Klenerman
authors.forename: Graeme J M
authors.initials: GJ
authors.lastname: Alexander
mesh_terms: D015704:CD4 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002450:Cell Communication; D005260:Female; D016174:Hepacivirus / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000821:virology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D015704:CD4 Antigens; D015375:Receptors, Interleukin-2