Circulating CD4+ CD25+ regulatory T cells correlate with chronic hepatitis B infection

Abstract

Summary: Circulating CD4⁺ CD25⁺ regulatory T cells (Tregs) have been demonstrated to maintain immunotolerance and suppress the antigen‐specific or antigen‐non‐specific T‐cell responses, but their role in chronic hepatitis B (CHB) infection in humans has not been well characterized. In this study, we analysed the frequency and phenotypic characteristics of CD4⁺ CD25⁺ Tregs in patients of different hepatitis B virus (HBV) infection status, and investigated the effect of Tregs on antiviral immune responses in CHB patients, and the mechanism of this effect. A total of 137 subjects, including 79 CHB patients, 26 asymptomatic HBV carriers (ASCs), 12 acute hepatitis B (AHB) patients and 20 healthy controls, were enrolled in the study. We found that the frequency of CD4⁺ CD25^high Tregs in AHB patients was comparable to that in healthy controls, while it was significantly increased in CHB patients. CD4⁺ CD25⁺ Tregs produced interleukin (IL)‐10 but little or no interferon (IFN)‐γ under anti‐CD3 stimulation. In CHB patients, the frequency of CD4⁺ CD25^high Tregs positively correlated with serum viral load, and the Tregs were capable of suppressing the proliferation and IFN‐γ production of autologous peripheral blood mononuclear cells (PBMC) mediated by HBV antigen stimulation in vitro. However, combined administration of anti‐programmed death‐1 (PD‐1) and anti‐cytotoxic lymphocyte antigen‐4 (CTLA‐4) monoclonal antibody slightly enhanced the cellular proliferation and significantly increased the IFN‐γ production of PBMC cocultured with Tregs at a ratio of 2 : 1. Thus, the frequency of circulating CD4⁺ CD25⁺ Tregs is increased in patients with CHB, and this may play an important role in viral persistence by modulating virus‐specific immune responses.