LAG3+ erythroid progenitor cells inhibit HBsAg seroclearance during finite pegylated interferon treatment through LAG3 and TGF-?
LAG3+ erythroid progenitor cells inhibit HBsAg seroclearance during finite pegylated interferon treatment through LAG3 and TGF-?
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DOI：
10.1016/j.antiviral.2023.105592
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发表时间：
2023-04-07
影响因子：
7.6
通讯作者：
Gao, Zhi-Liang
中科院分区：
文献类型：
--
作者：
Pang, Xiu-Qing;Li, Xing;Gao, Zhi-Liang
乙型肝炎病毒（HBV）治疗的理想目标——乙肝表面抗原（HBsAg）的血清清除并不容易实现。贫血是慢性乙型肝炎（CHB）患者的另一个常见问题，它导致红细胞祖细胞（EPCs）升高和癌症的免疫抑制。本研究探讨了EPCs在聚乙二醇化干扰素- α (PEG-IFN)治疗后HBsAg血清清除中的作用。流式细胞术和免疫荧光检测发现慢性乙型肝炎患者和AAV/ HBV小鼠模型在循环和肝脏中存在CD45+EPC积累。Wright-Giemsa染色显示，与对照细胞相比，这些病理CD45+EPCs表现为红细胞升高，形态相对不成熟，不典型细胞。在有限PEG-IFN治疗期间，CD45+EPCs与免疫耐受和HBsAg血清清除率降低有关。CD45+EPCs抑制抗原非特异性T细胞活化和hbv特异性CD8+T细胞，部分通过转化生长因子β (tgf - β)。RNA-seq显示，与脐带血的CD45-EPCs和CD45+EPCs相比，CHB患者的CD45+EPCs具有不同的基因表达谱。值得注意的是，来自CHB患者的CD45+EPCs表达高水平的淋巴细胞激活基因3 (LAG3)，这是一种免疫检查点分子，因此被定义为LAG3+EPCs。LAG3+EPCs通过LAG3降低抗原提呈细胞的功能，这是LAG3+EPCs抑制hbv特异性CD8+T细胞的另一种机制。在AAV/HBV小鼠模型中，抗lag3和抗tgf - β联合治疗降低了PEG-IFN治疗期间血清HBeAg、HBV DNA水平和HBsAg水平，以及肝细胞中HBsAg的表达。结论：LAG3+EPCs抑制PEG-IFN治疗对LAG3和tgf - β诱导的HBsAg血清清除率的影响。抗lag3、抗tgf - β和PEG-IFN联合治疗可能促进HBV清除。
HBsAg seroclearance, the ideal aim of anti-hepatitis B virus (HBV) treatment, cannot be achieved easily. Anemia is another common issue for chronic hepatitis B (CHB) patients, which leads to elevation of erythroid progenitor cells (EPCs) and immune suppression in cancer. This study investigated the role of EPCs in HBsAg seroclearance following pegylated interferon-alpha (PEG-IFN) treatment. CD45+EPC accumulation in CHB patients and an AAV/ HBV mice model was found in the circulation and liver by flow cytometry and immunofluorescence tests. Wright-Giemsa staining showed that these pathological CD45+EPCs presented elevated erythroid cells with relative immature morphologies and atypical cells compared with the control cells. CD45+EPCs were associated with immune tolerance and decreased HBsAg seroclearance during finite PEG-IFN treatment. CD45+EPCs suppressed antigen non-specific T cell activation and HBV-specific CD8+T cells, partially through transforming growth factor beta (TGF-beta). RNA-seq revealed that CD45+EPCs in patients with CHB presented a distinct gene expression profile compared with CD45-EPCs and CD45+EPCs from cord blood. Notably, CD45+EPCs from patients with CHB expressed high level of Lymphocyte-activation gene 3 (LAG3), an immune checkpoint molecule, and were then defined as LAG3+EPCs. LAG3+EPCs diminished the function of antigen presenting cells through LAG3, which was another mechanism by which LAG3+EPCs' suppressed HBV-specific CD8+T cells. Anti-LAG3 and anti-TGF-beta combination treatment decreased serum HBeAg, HBV DNA levels and HBsAg level, as well as HBsAg-expression in hepatocytes during PEG-IFN treatment in the AAV/HBV mice model. Conclusions: LAG3+EPCs inhibited the efficacy of PEG-IFN treatment on HBsAg seroclearance induced by LAG3 and TGF-beta. Anti-LAG3, anti-TGF-beta and PEG-IFN combination treatment might facilitate HBV clearance.