Regulatory T cells contribute to the impaired immune response in patients with chronic hepatitis B virus infection

Chronic hepatitis B virus (HBV) infection is characterized by a weak immune response to HBV. Regulatory T cells (T-reg) can suppress the function of effector T cells and may thus be key players in this impaired immune response. Changes in the functionality or number of T-reg could explain the decreased antiviral response in chronic HBV patients. To investigate the role of T-reg in chronic HBV infection, we compared the proportional frequency and functionality of T-reg in peripheral blood of 50 chronic HBV patients, 23 healthy controls, and 9 individuals with a resolved HBV infection. A higher percentage of T-reg, defined as CD4, CD25, CD45RO, and cytotoxic T-lymphocyte-associated antigen 4-positive cells, was detected within the population of CD4(+) cells in peripheral blood of chronic HBV patients compared with healthy controls and individuals with a resolved HBV infection. Accordingly, chronic HBV patients displayed a higher FoxP3 messenger RNA level than healthy controls. Depletion of CD25(+) cells from peripheral blood mononuclear cells (PBMC) of chronic HBV patients resulted in an enhanced proliferation after stimulation with HBV core antigen. Reconstitution of these depleted PBMC with CD4(+)CD25(+) T-reg resulted in a dose-dependent reduction of both HBV-specific proliferation and interferon gamma production. In conclusion, chronic HBV patients harbor an increased percentage of T-reg in peripheral blood compared with controls. T-reg have an immunosuppressive effect on HBV-specific T helper cells. The presence of HBV-specific Treg could contribute to an inadequate immune response against the virus, leading to chronic infection.