Objective Hepatitis B virus (HBV)-specific T cells are main effector cells in the control of HBV infection and hepatitis B surface antigen (HBsAg) is suggested to be a critical factor in the impaired immune response, a hallmark of chronic HBV infection. In addition to HBsAg, other viral markers such as hepatitis B core-related antigen (HBcrAg) are available, but their potential association with HBV-specific immune responses is not defined yet, which will be important if these markers are used for patient stratification for novel therapies aimed at functional HBV cure. Design We analysed T cell responses in 92 patients with hepatitis B e antigen negative chronic HBV infection with different HBsAg and HBcrAg levels. Overlapping peptides were used for in vitro response analyses (n=57), and HBV core18-specific and polymerase (pol)455-specific CD8+ T cells were assessed in human leukocyte antigen (HLA)-A*02 patients (n=35). In addition, in vitro responsiveness to anti-programmed cell death-ligand 1 (anti-PD-L1) was investigated. Results HBV-specific T cell responses were not affected by HBsAg levels, but rather by age and CD4+ T cell responses were highest in patients with low HBcrAg levels. The phenotypes and functionality of HBV core18-specific and pol455-specific CD8+ T cells differed, but HBsAg and HBcrAg levels did not affect their profiles. Blocking with anti-PD-L1 could restore HBV-specific T cells, but the effect was significantly higher in T cells isolated from patients with low HBsAg and in particular low HBcrAg. Conclusion Our data suggest that age and HBcrAg rather than HBsAg, are associated with HBV-specific T cell responses. Finally, very low antigen levels indicated by HBsAg and in particular HBcrAg may influence T cell response to checkpoint inhibition. All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to the study are included in the article or uploaded as supplementary information. As requested by reviewer 2 we deleted some redundant suplemnetary figure. Howeverm, the data can always be requested.

中文翻译：

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HBsAg和HBcrAg水平对慢性乙型肝炎病毒感染患者HBV特异性T细胞表型和功能的影响

目的乙型肝炎病毒（HBV）特异性T细胞是控制HBV感染的主要效应细胞，乙型肝炎表面抗原（HBsAg）被认为是慢性HBV感染的标志性免疫反应受损的关键因素。除了 HBsAg，还有其他病毒标志物，如乙型肝炎核心相关抗原 (HBcrAg)，但尚未确定它们与 HBV 特异性免疫反应的潜在关联，如果这些标志物用于患者分层，这一点将很重要针对功能性HBV治愈的新疗法。设计 我们分析了 92 名具有不同 HBsAg 和 HBcrAg 水平的乙型肝炎 e 抗原阴性慢性 HBV 感染患者的 T 细胞反应。重叠肽用于体外反应分析（n=57），在人类白细胞抗原 (HLA)-A*02 患者 (n=35) 中评估了 HBV core18 特异性和聚合酶 (pol)455 特异性 CD8+ T 细胞。此外，还研究了对抗程序性细胞死亡配体 1（抗 PD-L1）的体外反应性。结果 HBV 特异性 T 细胞反应不受 HBsAg 水平的影响，但受年龄和 CD4+ T 细胞反应在 HBcrAg 水平低的患者中最高。HBV core18 特异性和 pol455 特异性 CD8+ T 细胞的表型和功能不同，但 HBsAg 和 HBcrAg 水平不影响其特征。用抗 PD-L1 阻断可以恢复 HBV 特异性 T 细胞，但在从低 HBsAg 尤其是低 HBcrAg 患者分离的 T 细胞中效果显着更高。结论 我们的数据表明年龄和 HBcrAg 而不是 HBsAg，与 HBV 特异性 T 细胞反应有关。最后，HBsAg 尤其是 HBcrAg 表明的非常低的抗原水平可能会影响 T 细胞对检查点抑制的反应。所有与研究相关的数据都包含在文章中或作为补充信息上传。所有与研究相关的数据都包含在文章中或作为补充信息上传。根据审稿人 2 的要求，我们删除了一些多余的补充图。但是，始终可以请求数据。根据审稿人 2 的要求，我们删除了一些多余的补充图。但是，始终可以请求数据。根据审稿人 2 的要求，我们删除了一些多余的补充图。但是，始终可以请求数据。