PD-1 blockade partially recovers dysfunctional virus-specific B cells in chronic hepatitis B infection
PD-1 blockade partially recovers dysfunctional virus-specific B cells in chronic hepatitis B infection
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DOI：
10.1172/jci121957
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发表时间：
2018-10-01
影响因子：
15.9
通讯作者：
Bertoletti, Antonio
中科院分区：
文献类型：
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作者：
Salimzadeh, Loghman;Le Bert, Nina;Bertoletti, Antonio
慢性乙型肝炎病毒（CHB）感染抑制病毒特异性T细胞，但其对体液免疫的影响分析甚少。在这里，我们开发了一种双染色方法，利用荧光染料标记的乙型肝炎病毒（HBV）表面抗原（HBsAg）作为“诱饵”，对HBsAg特异性B细胞进行特异性体外检测，并分析其数量、功能和表型。我们研究了健康接种者（n = 18）和缓解（n = 21）、急性（n = 11）或慢性（n = 96） HBV感染的患者，观察到循环hbsag特异性B细胞的频率与HBV感染状态无关。相比之下，血清HBsAg的存在影响了HBsAg特异性B细胞的功能和表型，这些细胞无法在体外成熟为ab分泌细胞，并且显示出与过度活化（CD21(lo)）和衰竭（PD-1）相关的标志物的表达增加。重要的是，B细胞的改变并不局限于hbsag特异性B细胞，而是影响全球B细胞群。通过细胞因子IL-2和IL-21与表达cd40l的饲养细胞结合的方法可以部分恢复hbsag特异性B细胞的成熟，并通过添加抗PD-1抗体进一步增强。总之，HBV感染对全球和HBV特异性体液免疫有显著影响，但hbsag特异性B细胞可通过B细胞成熟细胞因子和PD-1阻断而部分恢复。
Chronic HBV (CHB) infection suppresses virus-specific T cells, but its impact on humoral immunity has been poorly analyzed. Here, we developed a dual-staining method that utilizes hepatitis B virus (HBV) surface antigens (HBsAg) labeled with fluorochromes as "baits" for specific ex vivo detection of HBsAg-specific B cells and analysis of their quantity, function, and phenotype. We studied healthy vaccinated subjects (n = 18) and patients with resolved (n = 21), acute (n = 11), or chronic (n = 96) HBV infection and observed that frequencies of circulating HBsAg-specific B cells were independent of HBV infection status. In contrast, the presence of serum HBsAg affected function and phenotype of HBsAg-specific B cells that were unable to mature in vitro into Ab-secreting cells and displayed an increased expression of markers linked to hyperactivation (CD21(lo)) and exhaustion (PD-1). Importantly, B cell alterations were not limited to HBsAg-specific B cells, but affected the global B cell population. HBsAg-specific B cell maturation could be partially restored by a method involving the combination of the cytokines IL-2 and IL-21 and CD40L-expressing feeder cells and was further boosted by the addition of anti-PD-1 Abs. In conclusion, HBV infection has a marked impact on global and HBV-specific humoral immunity, yet HBsAg-specific B cells are amenable to a partial rescue by B cell-maturing cytokines and PD-1 blockade.