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+ CD25high 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+ CD25high 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.

Augmentation of Hepatitis B Virus-Specific Cellular Immunity with Programmed Death Receptor-1/Programmed Death Receptor-L1 Blockade in Hepatitis B Virus and HIV/Hepatitis B Virus Coinfected Patients Treated with Adefovir

“…36,37 In our study, a large proportion of peripheral Tregs observed in the periphery of CHB patients also express high levels of PD-1, even after 48 weeks of adefovir and suppression of HBV VL, predisposing them to impaired responsiveness to antigenic stimulation or apoptosis soon after activation. 26,27 Additionally, we were able to demonstrate diminished but still high levels of FoxP3 While other studies have examined the role of a PD-1 blockade in regulating Tregs for hepatitis C virus infection, our study demonstrated the effectiveness of PD-1 blockade in HIV/HBV-infected patients. 38 Since many effector T cells and Tregs in CHB patients express PD-1, it is unclear whether the enhancement of HBV-specific immunity observed in our patients is due to a direct effect on T cells, T effector memory cells, or both.…”

“…[25][26][27] Treg expansion has also been demonstrated in HIV viremic patients, 13 but the relationship between HBV replication and Treg expansion has not been studied in detail in HIV/HBV-coinfected patients. In addition, to our knowledge, no studies have examined a functional role for Tregs in CHB patients before and after control of HBV replication.…”

“…12,13 Recent studies, however, have shown a higher percentage of T regulatory cells (Treg) in the peripheral blood of CHB patients as compared to uninfected individuals 14 and a positive correlation between Treg activity and HBV viral load among HBeAg-negative CHB patients. 15 Tregs, demarcated by CD4 + CD24 + FoxP3 + expression, 16 inhibit effective virus-specific immune responses 17,18 and can also express programmed death receptor-1 (PD-1), which further deters immune responses when expressed on CD4 + , CD8 + , NK T cells, monocytes, or B cells.…”

Hepatic CD206-positive macrophages express amphiregulin to promote the immunosuppressive activity of regulatory T cells in HBV infection

“…However, impaired immune response contributes to the failure of viral clearance. Immunosuppressive CD4 + Foxp3 + T regs have been associated with the progression and prognosis of HBV infection by previous studies [7][8][9]. Studies have demonstrated the negative role of T regs in immune response to HBV infection, including suppression of HBV-specific Th cells, suppression of proliferation of virus-specific CD8 + T cells [10][11][12], and reduction of IFN-g production [7].…”

siRNA-mediated knockdown of FoxP3 promotes the ratio of T-helper 1 (Th1) to Th2 in chronic hepatitis B patients

“…Meanwhile, during the research on chronic HBV infection, it was found that the frequency of CD4+CD25+ Tregs significantly increased in peripheral blood of CHB patients totally when compared with healthy controls, and had a positive correlation with serum HBV DNA load in CHB patients, with >10 7 copies/ml serum HBV DNA. Furthermore, the depletion of CD4+CD25+Tregs leads to the increase of HBV Ag-stimulated IFN-γ production and cellular proliferation of peripheral blood mononuclear cells (PBMCs) from HBV-infected patients, and co-culture of CD4+CD25+Tregs with effector cells significantly suppressed HBV Ag-stimulated IFN-γ production and cellular proliferation (8,9). Thus, although the exact mechanism has not been well defined yet, Tregs may play an important role in HBV persistence by modulating virus-specific immune responses.…”