Blockade of programmed death receptor-1 signaling restores expression of mostly proinflammatory cytokines in anergic cytomegalovirus-specific T cells
Blockade of programmed death receptor-1 signaling restores expression of mostly proinflammatory cytokines in anergic cytomegalovirus-specific T cells
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DOI：
10.1111/tid.12025
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发表时间：
2013-02-01
影响因子：
2.6
通讯作者：
Hirsch, H. H.
中科院分区：
文献类型：
--
作者：
Dirks, J.;Egli, A.;Hirsch, H. H.
背景程序性死亡受体-1（PD-1）损害巨细胞病毒（CMV）特异性T细胞应答，并与移植后CMV病毒血症有关。PD-1阳性CMV特异性T细胞的功能和增殖能力受损可通过抗体介导的PD-1信号传导阻断来逆转。然而，知识是有限的，在“细胞因子组”表达谱的变化与功能衰竭的逆转。通过27-plex Luminex技术分析“细胞因子组”，比较CMV特异性T细胞上具有低（n = 5）和高（n = 5）PD-1表达的肾移植受者。检测通过PD-配体（PD-L）抗体阻断PD-1对细胞因子表达恢复的影响。在CMV特异性T细胞上具有高PD-1表达的患者中，CMV特异性细胞因子释放和增殖较低。抗体介导的CMV刺激样品中PD-L的阻断恢复了白细胞介素（IL）-1 β、IL-2、IL-6、IL-9、IL-10、粒细胞集落刺激因子、干扰素-γ、巨噬细胞炎性蛋白-1 α和肿瘤坏死因子-α的表达水平。相比之下，在对照组、PD-1低表达患者或葡萄球菌肠毒素B刺激的细胞中未观察到显著影响。总之，该初步研究提供了证据，证明CMV特异性T细胞上的高PD-1表达以抗原特异性方式积极损害增殖和“细胞因子组”应答。重要的是，PD-L的阻断恢复了CMV特异性T细胞增殖和一组不同促炎和/或1型细胞因子的表达，这表明了一种常见但未知的调控原理。我们得出结论，PD-1耗竭是可逆的，可能适用于离体治疗和可能的体内操作。然而，详细的知识的差异效应的“细胞因子”将是必要的，以增加安全性和有效性的这种操作。
Background. Programmed death receptor-1 (PD-1) compromises cytomegalovirus (CMV)-specific T-cell responses and has been linked to CMV viremia after transplantation. An impaired functional and proliferative capacity of PD-1-positive CMV-specific T cells may be reversed by the antibody-mediated blockade of PD-1 signaling. However, knowledge is limited on changes in "cytokinome" expression profiles associated with reversal of functional exhaustion.Methods. The "cytokinome" was analyzed by 27-plex Luminex technology comparing renal transplant recipients with low (n = 5) and high (n = 5) PD-1 expression on CMV-specific T cells. The effect of blocking PD-1 by PD-ligand (PD-L) antibodies on restoration of cytokine expression was examined.Results. CMV-specific cytokine release and proliferation was lower in patients with high PD-1 expression on CMV-specific T cells. Antibody-mediated blockade of PD-L in CMV-stimulated samples restored expression levels of interleukin (IL)-1 beta, IL-2, IL-6, IL-9, IL-10, granulocyte colony-stimulating factor, interferon-gamma, macrophage inflammatory protein-1 alpha, and tumor necrosis factor-alpha. By contrast, no profound effect was observed for controls or patients with low PD-1 expression, or in staphylococcal enterotoxin B-stimulated cells.Conclusion. Taken together, this pilot study provides evidence that a high PD-1 expression on CMV-specific T cells actively impairs proliferation and "cytokinome" responses in an antigen-specific manner. Importantly, blockade of PD-L restores CMV-specific T-cell proliferation and expression of a panel of different proinflammatory and/or type 1 cytokines, suggesting a common but as yet unknown regulatory principle. We conclude that PD-1 exhaustion is reversible and potentially amenable to therapeutic ex vivo and possibly in vivo manipulation. However, detailed knowledge of the differential effects on the "cytokinome" will be necessary to increase the safety and the efficacy of such manipulations.