Influence of PD-L1 cross-linking on cell death in PD-L1-expressing cell lines and bovine lymphocytes
Influence of PD-L1 cross-linking on cell death in PD-L1-expressing cell lines and bovine lymphocytes
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DOI：
10.1111/imm.12243
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发表时间：
2014-08-01
期刊：
影响因子：
6.4
通讯作者：
Ohashi, Kazuhiko
中科院分区：
文献类型：
--
作者：
Ikebuchi, Ryoyo;Konnai, Satoru;Ohashi, Kazuhiko
程序性死亡配体1（PD-L1）阻断被认为是一种重新激活表达程序性死亡-1（PD-1）的耗竭T细胞的新策略。然而，抗PD-L1单克隆抗体（mAb）或PD-1-免疫球蛋白融合蛋白（PD-1-IG）交联PD-L1后，PD-L1介导的抑制性信号传导机制仍不清楚，尽管其可能诱导常规免疫反应所需的PD-L1（+）细胞的细胞死亡。在本研究中，在表达PD-L1的细胞系和牛淋巴细胞中检测了PD-1-IG或抗PD-L1 mAb处理，以研究处理是否诱导免疫再激活或PD-L1介导的细胞死亡。通过PD-1-IG或抗PD-L1 mAb进行的PD-L1交联主要增加PD-L1（高）细胞中的死细胞数量，但不增加PD-L1（低）细胞中的死细胞数量;这些细胞由Cos-7细胞制备，其中通过转染诱导牛PD-L1表达。PD-L1介导的细胞死亡也发生在用仅编码PD-L1胞外区的载体转染的Cos-7和HeLa细胞中。在牛淋巴细胞中，抗PD-L1 mAb处理上调了干扰素-γ（IFN-γ）的产生，而PD-1-IG处理降低了这种细胞因子的产生和细胞增殖。PD-1-IG处理未降低B细胞耗竭的外周血单核细胞中IFN-γ的产生，PD-1-IG处理增加了PD-L1（+）B细胞中死亡细胞的百分比，表明PD-1-Ig诱导的牛淋巴细胞免疫抑制可能是由PD-L1介导的B细胞死亡引起的。这项研究为理解PD-L1信号转导提供了新的信息。
Programmed death-ligand 1 (PD-L1) blockade is accepted as a novel strategy for the reactivation of exhausted T cells that express programmed death-1 (PD-1). However, the mechanism of PD-L1-mediated inhibitory signalling after PD-L1 cross-linking by anti-PD-L1 monoclonal antibody (mAb) or PD-1-immunogloblin fusion protein (PD-1-Ig) is still unknown, although it may induce cell death of PD-L1(+) cells required for regular immune reactions. In this study, PD-1-Ig or anti-PD-L1 mAb treatment was tested in cell lines that expressed PD-L1 and bovine lymphocytes to investigate whether the treatment induces immune reactivation or PD-L1-mediated cell death. PD-L1 cross-linking by PD-1-Ig or anti-PD-L1 mAb primarily increased the number of dead cells in PD-L1(high) cells, but not in PD-L1(low) cells; these cells were prepared from Cos-7 cells in which bovine PD-L1 expression was induced by transfection. The PD-L1-mediated cell death also occurred in Cos-7 and HeLa cells transfected with vectors only encoding the extracellular region of PD-L1. In bovine lymphocytes, the anti-PD-L1 mAb treatment up-regulated interferon-gamma (IFN-gamma) production, whereas PD-1-Ig treatment decreased this cytokine production and cell proliferation. The IFN-gamma production in B-cell-depleted peripheral blood mononuclear cells was not reduced by PD-1-Ig treatment and the percentages of dead cells in PD-L1(+) B cells were increased by PD-1-Ig treatment, indicating that PD-1-Ig-induced immunosuppression in bovine lymphocytes could be caused by PD-L1-mediated B-cell death. This study provides novel information for the understanding of signalling through PD-L1.