Restoration of HBV-specific CD8+T cell function by PD-1 blockade in inactive carrier patients is linked to T cell differentiation
Restoration of HBV-specific CD8+T cell function by PD-1 blockade in inactive carrier patients is linked to T cell differentiation
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DOI：
10.1016/j.jhep.2014.07.005
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发表时间：
2014-12-01
影响因子：
25.7
通讯作者：
Thimme, Robert
中科院分区：
文献类型：
--
作者：
Bengsch, Bertram;Martin, Bianca;Thimme, Robert
背景和目标：在慢性感染中，HBV特异性CD 8 + T细胞耗竭导致的几种抑制性信号传导途径的上调被认为是导致病毒持续存在的原因。阻断抑制性受体以重振衰竭的T细胞功能是一种有前途的新型治疗方法。然而，关于单个抑制途径对HBV特异性CD 8 + T细胞衰竭的相对贡献以及抑制性受体阻断对慢性HBV T细胞功能恢复的影响，目前几乎没有信息。方法：对98例HLA-A2+慢性感染患者进行了离体分析，以了解HBV特异性CD 8 + T细胞反应、多种抑制性受体的表达和T细胞分化标志物。靶向PD-1，2B 4，Tim-3，CTLA-4和BTLA的抑制性受体阻断剂的效果进行了评估在vitro.Results：在我们的队列中，体外HBV特异性CD 8 + T细胞反应被确定优先在HBeAg患者低ALT和低病毒载量（非活性载体）。我们观察到由PD-1主导的抑制性受体表达的清晰层次。对抑制性受体阻断的反应是异质性的。与其他抑制性受体的阻断相比，PD-1通路的阻断导致功能的最强增强。值得注意的是，PD-1阻断的积极作用与中间T细胞differentiation.Conclusions：尽管HBV特异性CD 8 + T细胞表达多种抑制性受体，但PD-1对阻断的表达和反应占主导地位。然而，PD-1表达并不能预测对阻断的反应。相反，对阻断的反应与中间T细胞分化相关。这些发现对于我们理解抑制性受体阻断作为一种新的治疗策略具有重要意义。(C)2014年由Elsevier B出版。代表欧洲肝脏研究协会。
Background & Aims: The upregulation of several inhibitory signalling pathways by exhausted HBV-specific CD8+ T cells in chronic infection is thought to contribute to viral persistence. Blockade of inhibitory receptors to reinvigorate exhausted T cell function is a promising novel therapeutic approach. However, little information is available regarding the relative contribution of individual inhibitory pathways to HBV-specific CD8+ T cell failure and the impact of inhibitory receptor blockade on restoration of T cell function in chronic HBV.Methods: 98 HLA-A2+ chronically infected patients were analysed ex vivo for HBV-specific CD8+ T cell responses, the expression of multiple inhibitory receptors and T cell differentiation markers. The effects of inhibitory receptor blockade targeting PD-1, 2B4, Tim-3, CTLA-4, and BTLA were assessed in vitro.Results: In our cohort, ex vivo HBV-specific CD8+ T cell responses were identified preferentially in HBeAg patients with low ALT and low viral load (inactive carriers). We observed a clear hierarchy of inhibitory receptor expression dominated by PD-1. The response to inhibitory receptor blockade was heterogeneous. Compared to the blockade of other inhibitory receptors, blockade of the PD-1 pathway resulted in the strongest increase in function. Of note, a positive effect of PD-1 blockade was linked to intermediate T cell differentiation.Conclusions: Despite the expression of multiple inhibitory receptors by HBV-specific CD8+ T cells, expression and response to blockade was dominated by PD-1. However, PD-1 expression did not predict response to blockade. Rather, response to blockade was associated with intermediate T cell differentiation. These findings have important implications for our understanding of inhibitory receptor blockade as a novel therapeutic strategy. (C) 2014 Published by Elsevier B. V. on behalf of the European Association for the Study of the Liver.