白细胞介素-35 调节慢性乙型肝炎病毒感染中病毒特异性 CD4+CD25+CD127regulatory T 细胞和辅助性 T 细胞 17 之间的平衡。
Interleukin-35 modulates the balance between viral specific CD4CD25CD127 regulatory T cells and T helper 17 cells in chronic hepatitis B virus infection.
机构信息
Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, No. 218 Ziqiang Street, Nanguan District, Changchun, 130041, Jilin Province, China.
出版信息
Virol J. 2019 Apr 16;16(1):48. doi: 10.1186/s12985-019-1158-0.
BACKGROUND
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. 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.
METHODS
A 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 CD4CD25CD127 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.
RESULTS
Peripheral 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.
CONCLUSION
Our findings indicated that IL-35 regulation to viral specific Tregs/Th17 balance may contribute to viral persistence in chronic HBV infection.
背景
白细胞介素 (IL)-35 调节调节性 T 细胞 (Tregs) 和辅助性 T 细胞 17 (Th17) 之间的失衡，成为自身免疫性疾病、癌症和传染病的重要调节剂。我们之前的研究表明 IL-35 在慢性乙型肝炎病毒 (HBV) 感染中有免疫抑制活性。因此，本研究旨在探讨 IL-35 对慢性 HBV 感染中病毒特异性 Tregs/Th17 细胞平衡的调节作用。
方法
共纳入 44 名 HLA-A2 限制性慢性 HBV 感染患者，包括 21 名慢性乙型肝炎 (CHB) 患者和 23 名无症状 HBV 携带者 (ASC)。用重组 IL-35 刺激纯化的 CD4 T 细胞或 CD4CD25CD127 Tregs。通过流式细胞术测定 HBV 核心抗原特异性 Tregs 和 Th17 细胞。通过实时 PCR 测定 FoxP3 和 RORγt mRNA。通过 ELISA 检测细胞因子产生 (IL-10 和 IL-17)。
结果
CHB 和 ASC 患者外周血病毒特异性 Tregs 无差异。然而，CHB 患者中发现病毒特异性 Th17 细胞比例增加，导致 CHB 患者 Tregs/Th17 比值降低。IL-35 刺激可增加 CHB 和 ASC 患者中病毒特异性 Tregs 的频率，但不增加 Th17 细胞的频率，导致两组 Tregs/Th17 比值升高。这一过程伴随着 FoxP3 mRNA 表达增加和 IL-10 产生增加，以及 CHB 患者纯化的 CD4 T 细胞中 IL-17 分泌减少和 STAT3 磷酸化减少。此外，IL-35 刺激抑制了 CHB 患者 Tregs 向 Th17 样表型分化。有效的抗 HBV 治疗并未影响 CHB 患者中病毒特异性 Tregs/Th17 细胞的频率或 IL-35 的表达，但降低了体外 CD4 T 细胞或 Tregs 对 IL-35 刺激的反应性。
结论
我们的研究结果表明，IL-35 对病毒特异性 Tregs/Th17 平衡的调节可能导致慢性 HBV 感染中的病毒持续存在。
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