T follicular helper cells improve the response of patients with chronic hepatitis B to interferon by promoting HBsAb production
T follicular helper cells improve the response of patients with chronic hepatitis B to interferon by promoting HBsAb production
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DOI：
10.1007/s00535-021-01840-w
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发表时间：
2022-01-06
影响因子：
6.3
通讯作者：
Jiang, Yanfang
中科院分区：
文献类型：
--
作者：
Liu, Yong;Hu, Xintong;Jiang, Yanfang
背景和目的乙型肝炎表面抗原（HBsAg）血清转化被认为是治疗慢性乙型肝炎病毒（HBV）感染的最佳结果。在这项研究中，我们旨在确定聚乙二醇化干扰素α (peg - ifn - α)提高慢性乙型肝炎（CHB）患者血清转换率的细胞和分子机制。方法采用流式细胞术检测15例健康人及45例慢性乙型肝炎患者的循环T滤泡辅助细胞（TFH），观察循环TFH细胞在标准48周peg - ifn - α单药治疗方案中的作用[完全缓解组（CRG）、不完全缓解组（ICRG）和无缓解组（NRG）1]。此外，通过共培养实验评估不同TFH亚群激活B细胞和刺激IgG产生的能力。结果纵向分析显示，与NRG和ICRG相比，CRG中CD40L(+) CD4(+) CXCR5(+) TFH细胞数量特异性显著增加。体外共培养实验结果显示，阻断CD40-CD40L信号通路，而不阻断ICOS-ICOSL信号通路，特异性抑制b细胞活化和IgG产生。HBV可能通过增强抑制性调节性t细胞活性而损害TFH细胞功能。转录组分析进一步揭示了从CRG分离的TFH细胞中CD40L上调，而ICOS未上调。结论经peg - ifn - α单药治疗的CHB患者，TFH细胞，特别是CD40L表达的TFH细胞，可刺激b细胞分化，提高HBsAg血清转化率。
Background and aims Hepatitis B surface antigen (HBsAg) seroconversion is considered the optimal outcome of the treatment of chronic hepatitis B virus (HBV) infection. In this study, we aimed to determine the cellular and molecular mechanisms by which pegylated interferon alpha (PEG-IFN-alpha) improves the seroconversion rate in patients with chronic hepatitis B (CHB).Methods Flow cytometry was performed using circulating T follicular helper (TFH) cells from 15 healthy individuals and 45 patients with CHB presenting different treatment responses [complete response group (CRG), incomplete response group (ICRG), and nonresponse group (NRG)1 to the standard 48-week regimen of PEG-IFN-alpha monotherapy to examine the significance of circulating TFH cells in the therapeutic response of patients with CHB to PEG-IFN-alpha. In addition, the capacities of different TFH subsets to activate B cells and stimulate IgG production were assessed by performing coculture experiments.Results Longitudinal analysis revealed specific and significant increases in the numbers of CD40L(+) CD4(+) CXCR5(+) TFH cells in the CRG compared with the NRG and ICRG. According to the results of in vitro coculture experiments, blocking CD40-CD40L signaling, but not ICOS-ICOSL signaling, specifically inhibits B-cell activation and IgG production. HBV may impair TFH cell function by enhancing inhibitory regulatory T-cell activity. Transcriptome analysis further revealed the upregulation of CD40L, but not of ICOS, in TFH cells isolated from the CRG.Conclusions TFH cells, particularly those with CD40L expression, stimulate B-cell differentiation and improve the HBsAg seroconversion rate in patients with CHB treated with PEG-IFN-alpha monotherapy.