Abstract
BackgroundInterleukin (IL)-35 regulates imbalance between regulatory T cells (Tregs) and T helper (Th) 17 cells, leading to an important modulator in autoimmune disorder, cancer, and infectious diseases. Our previous study revealed an immunosuppressive activity of IL-35 in chronic hepatitis B virus (HBV) infection. Thus, the aim of the current study was to investigate the role of regulatory function of IL-35 to viral specific Tregs/Th17 cells balance in chronic HBV infection.MethodsA total of 44 HLA-A2 restricted chronic HBV infected patients, including 21 of chronic hepatitis B (CHB) and 23 of asymptomatic HBV carriers (ASC) were enrolled. Purified CD4+ T cells or CD4+CD25+CD127dim/− Tregs were stimulated with recombinant IL-35. HBV core antigen specific Tregs and Th17 cells were determined by flow cytometry. FoxP3 and RORγt mRNA was measured by real-time PCR. Cytokines production (IL-10 and IL-17) was investigated by ELISA.ResultsPeripheral viral specific Tregs was comparable between CHB and ASC. However, increased percentage of viral specific Th17 cells was found in CHB, leading to the reduction of Tregs/Th17 ratio in CHB patients. IL-35 stimulation elevated viral specific Tregs, but not Th17 cells frequency, in both CHB and ASC, resulting in the elevation of Tregs/Th17 ratio in both groups. This process was accompanied by increased expression of FoxP3 mRNA and IL-10 production, and decreased IL-17 secretion and STAT3 phosphorylation in purified CD4+ T cells. Moreover, IL-35 stimulation inhibited viral specific Th17-like phenotype differentiation from Tregs in CHB patients. Effective anti-HBV therapy did not affect viral specific Tregs/Th17 cells frequency or IL-35 expression in CHB patients, however, reduced responsiveness of CD4+ T cells or Tregs to IL-35 stimulation in vitro.ConclusionOur findings indicated that IL-35 regulation to viral specific Tregs/Th17 balance may contribute to viral persistence in chronic HBV infection.
Highlights
Interleukin (IL)-35 regulates imbalance between regulatory T cells (Tregs) and T helper (Th) 17 cells, leading to an important modulator in autoimmune disorder, cancer, and infectious diseases
Imbalance between hepatitis B virus (HBV) core-specific CD4+CD25+CD127dim/- Regulatory T cells (Tregs) and Th17 cells in chronic hepatitis B (CHB) and asymptomatic HBV carriers (ASC) peripheral blood mononuclear cells (PBMC) were isolated from all enrolled patients (21 CHB and 23 ASC), and were stimulated with HBc 18–27 peptide for 12 h
In the present study, an increased HBV core-specific Th17 cell response was found in CHB patients, leading to the reduction of viral specific Tregs/Th17 ratio in CHB patients when compared with ASC
Summary
Interleukin (IL)-35 regulates imbalance between regulatory T cells (Tregs) and T helper (Th) 17 cells, leading to an important modulator in autoimmune disorder, cancer, and infectious diseases. Our previous study revealed an immunosuppressive activity of IL-35 in chronic hepatitis B virus (HBV) infection. The aim of the current study was to investigate the role of regulatory function of IL-35 to viral specific Tregs/Th17 cells balance in chronic HBV infection. Chronic hepatitis B virus (HBV) infection is still a large public health problem, with approximate 350 million persistent infections all over the world [1]. Chronic HBV infection always leads to end-stage liver diseases, such as decompensated cirrhosis, severe hepatitis, and hepatocellular carcinoma (HCC), resulting in more than 1 million deaths annually worldwide [2]. HBV infection in infants or children always results in persistent infections, which manifested as weak or undetectable cellular immune responses [5]. The precise mechanism of T cell hyporesponsiveness and immune tolerance in chronic HBV infection is still not fully understood
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