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-γ) 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-γ-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.