Department of Infectious Diseases, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China; Institute of Viruses and Infectious Diseases, Nanjing University, Jiangsu, China.
Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China.
Antiviral Res. 2023 Aug;216:105665. doi: 10.1016/j.antiviral.2023.105665. Epub 2023 Jul 7.
Failure in curing chronic hepatitis B (CHB) caused by hepatitis B virus (HBV) can lead to functional impairment of B cells. Cytotoxic T-lymphocyte associated antigen 4 (CTLA4) regulates B cell and T follicular helper (Tfh) cell differentiation. In addition, Tfh cells play a critical role in helping B cells generate antibodies upon pathogen exposure. Here, we analyzed the global and HBsAg-specific B cells and circulating Tfh (cTfh) cells using samples from treatment-naïve and Peg-IFN-α-treated CHB patients and healthy subjects. Compared to healthy subjects, CTLA4 expression was significantly increased in cTfh cells, from CHB patients. The frequency of CTLA4cTfh2 cells was negatively correlated with that of HBsAg-specific resting memory B cells. Importantly, inhibition of CTLA4 restored HBsAb secretion and promoted plasma cell differentiation. In addition, CTLA4cTfh2 cells from CHB patients were ineffective in providing B cell help. Both expression of CTLA4 in cTfh and cTfh2 cells and ratios of CLTA4cTfh and CTLA4cTfh2 cells were significantly decreased in Peg-IFN-α-treated CHB patients who showed complete responses. Thus, our results highlighted that cTh2-biased T follicular helper cells could impede antiviral humoral responses during chronic HBV infection by upregulating CTLA4, suggesting that further optimizing potent Tfh cell responses may promote functional cure of CHB.
乙型肝炎病毒（HBV）导致的慢性乙型肝炎（CHB）治疗失败可导致 B 细胞功能受损。细胞毒性 T 淋巴细胞相关抗原 4（CTLA4）调节 B 细胞和滤泡辅助性 T 细胞（Tfh）分化。此外，Tfh 细胞在帮助 B 细胞产生抗体以应对病原体方面起着至关重要的作用。在这里，我们使用未经治疗和聚乙二醇干扰素-α（Peg-IFN-α）治疗的 CHB 患者和健康受试者的样本分析了总 B 细胞和 HBsAg 特异性 B 细胞以及循环滤泡辅助性 T 细胞（cTfh）。与健康受试者相比，cTfh 细胞中 CTLA4 的表达明显升高，来自 CHB 患者。CTLA4cTfh2 细胞的频率与 HBsAg 特异性静息记忆 B 细胞的频率呈负相关。重要的是，CTLA4 抑制可恢复 HBsAb 分泌并促进浆细胞分化。此外，CHB 患者的 CTLA4cTfh2 细胞在提供 B 细胞帮助方面无效。Peg-IFN-α 治疗的 CHB 患者中，CTLA4 在 cTfh 和 cTfh2 细胞中的表达以及 CTLA4cTfh 和 CTLA4cTfh2 细胞的比例均显著降低，这些患者表现出完全应答。因此，我们的结果强调，在慢性 HBV 感染期间，Th2 偏向的滤泡辅助性 T 细胞可通过上调 CTLA4 来阻碍抗病毒体液反应，这表明进一步优化有效的 Tfh 细胞反应可能促进 CHB 的功能性治愈。
