There is increasing evidence that interaction between programmed death 1 (PD-1) and its ligands PD-1 (PD-L1) plays a critical role in the pathology of acute graft-versus-host disease (aGVHD). However, the role of PD-L1 in the development of aGVHD has been controversial in recent mouse studies. In this study, we carried out studies in a murine aGVHD model to clarify the role of PD-L1 in aGVHD pathogenesis. We found that systemic overexpression of PD-L1 by hydrodynamic gene transfer (HGT) method in vivo ameliorates aGVHD-induced lethality in mice. Systemic overexpression of PD-L1 inhibits the donor T cells activation, effector memory status, as well as Th1 and Th17 cells responses in vivo. In addition, PD-L1 Ig treatment significantly suppressed T cells' proliferation, promoted T cells' apoptosis, and reduced pro-inflammatory cytokines expression by effector T cells in vitro in the stimulation of anti-CD3/CD28 and allogeneic dendritic cells. However, we found that PD-L1 overexpression did not affect Treg cells' differentiation in vivo and in vitro, depletion of Treg cells in PD-L1 HGT recipients did not aggravate aGVHD mortality. Therefore, our results demonstrated that systemic treatment with PD-L1 protein ameliorates aGVHD by suppressing effector but not regulatory T cell function. Our findings suggest that systemic treatment with PD-L1 may be a potential strategy to prevent or ameliorate aGVHD.

中文翻译：

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PD-L1通过抑制效应子而非调节性T细胞功能来减轻小鼠急性移植物抗宿主病。

越来越多的证据表明，程序性死亡1（PD-1）及其配体PD-1（PD-L1）之间的相互作用在急性移植物抗宿主病（aGVHD）的病理学中起着至关重要的作用。但是，PD-L1在aGVHD发育中的作用在最近的小鼠研究中一直存在争议。在这项研究中，我们进行了鼠aGVHD模型研究，以阐明PD-L1在aGVHD发病机理中的作用。我们发现通过体内流体动力学基因转移（HGT）方法的PD-L1的系统过度表达可改善aGVHD诱导的小鼠致死率。PD-L1的系统性过表达抑制体内的供体T细胞活化，效应记忆状态以及Th1和Th17细胞反应。另外，PD-L1 Ig处理可显着抑制T细胞增殖，促进T细胞凋亡，并通过效应T细胞在体外刺激抗CD3 / CD28和同种异体树突状细胞中降低促炎细胞因子的表达。但是，我们发现PD-L1的过表达在体内和体外均不影响Treg细胞的分化，PD-L1 HGT受体中Treg细胞的耗竭并没有加重aGVHD的死亡率。因此，我们的结果表明，用PD-L1蛋白进行全身性治疗可通过抑制效应子而非调节性T细胞功能来改善aGVHD。我们的发现表明，PD-L1的全身治疗可能是预防或改善aGVHD的潜在策略。PD-L1 HGT受体中Treg细胞的耗竭并没有加重aGVHD的死亡率。因此，我们的结果表明，用PD-L1蛋白进行全身性治疗可通过抑制效应子而非调节性T细胞功能来改善aGVHD。我们的发现表明，PD-L1的全身治疗可能是预防或改善aGVHD的潜在策略。PD-L1 HGT受体中Treg细胞的耗竭并没有加重aGVHD的死亡率。因此，我们的结果表明，用PD-L1蛋白进行全身性治疗可通过抑制效应子而非调节性T细胞功能来改善aGVHD。我们的发现表明，PD-L1的全身治疗可能是预防或改善aGVHD的潜在策略。