Inhibitory phenotype of HBV-specific CD4+ T-cells is characterized by high PD-1 expression but absent coregulation of multiple inhibitory molecules.
Inhibitory phenotype of HBV-specific CD4+ T-cells is characterized by high PD-1 expression but absent coregulation of multiple inhibitory molecules.
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DOI：
10.1371/journal.pone.0105703
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Jung MC
中科院分区：
文献类型：
--
作者：
Raziorrouh B;Heeg M;Kurktschiev P;Schraut W;Zachoval R;Wendtner C;Wächtler M;Spannagl M;Denk G;Ulsenheimer A;Bengsch B;Pircher H;Diepolder HM;Grüner NH;Jung MC
T 细胞耗竭似乎在慢性病毒感染期间 CD8+ T 细胞功能障碍中发挥着关键作用。然而，迄今为止，人们对慢性乙型肝炎病毒（CHB）感染期间CD4+ T细胞功能障碍的机制以及程序性死亡1（PD-1）等抑制分子在CD4+ T细胞衰竭中的作用知之甚少。使用新建立的 DRB1*01 限制性 MHC II 类四聚体，对来自外周血的病毒特异性 CD4+ T 细胞分析 PD-1、CTLA-4、TIM-3、CD244、KLRG1 等多种抑制分子以及定义 T 细胞分化等级的标记物 CCR7、CD45RA、CD57 和 CD127 的表达。通过研究 CD4+ T 细胞增殖和细胞因子产生的变化来确定体外 PD-L1/2 阻断的效果。慢性 HBV 感染期间 CD4+ T 细胞反应的特点是四聚体+CD4+ T 细胞频率降低、效应记忆表型、持续的 PD-1，但 CTLA-4、TIM-3、KLRG1 和 CD244 表达水平较低。 PD-1 阻断揭示了体外反应的个体化模式，几乎在病毒控制的治疗患者中，IFN-γ、IL-2 和 TNF-α 分泌部分增加，CD4+ T 细胞扩增增强。通过 MHC II 类四聚体技术，可以在 HBV 感染的不同过程中可靠地检测到 HBV 特异性 CD4+ T 细胞。慢性 HBV 期间的 CD4+ T 细胞功能障碍基本上与 PD-1 的强烈上调有关，但缺乏多种抑制性受体的共同调节。 PD-L1/2 中和部分导致 CD4+ T 细胞功能增强，并具有异质的 CD4+ T 细胞再生模式。
T-cell exhaustion seems to play a critical role in CD8+ T-cell dysfunction during chronic viral infections. However, up to now little is known about the mechanisms underlying CD4+ T-cell dysfunction during chronic hepatitis B virus (CHB) infection and the role of inhibitory molecules such as programmed death 1 (PD-1) for CD4+ T-cell failure. The expression of multiple inhibitory molecules such as PD-1, CTLA-4, TIM-3, CD244, KLRG1 and markers defining the grade of T-cell differentiation as CCR7, CD45RA, CD57 and CD127 were analyzed on virus-specific CD4+ T-cells from peripheral blood using a newly established DRB1*01-restricted MHC class II Tetramer. Effects of in vitro PD-L1/2 blockade were defined by investigating changes in CD4+ T-cell proliferation and cytokine production. CD4+ T-cell responses during chronic HBV infection was characterized by reduced Tetramer+CD4+ T-cell frequencies, effector memory phenotype, sustained PD-1 but low levels of CTLA-4, TIM-3, KLRG1 and CD244 expression. PD-1 blockade revealed individualized patterns of in vitro responsiveness with partly increased IFN-γ, IL-2 and TNF-α secretion as well as enhanced CD4+ T-cell expansion almost in treated patients with viral control. HBV-specific CD4+ T-cells are reliably detectable during different courses of HBV infection by MHC class II Tetramer technology. CD4+ T-cell dysfunction during chronic HBV is basically linked to strong PD-1 upregulation but absent coregulation of multiple inhibitory receptors. PD-L1/2 neutralization partly leads to enhanced CD4+ T-cell functionality with heterogeneous patterns of CD4+ T-cell rejunivation.
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DOI：
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发表时间：
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期刊：
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