Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality
Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality
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DOI：
10.1172/jci85796
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发表时间：
2016-07-01
影响因子：
15.9
通讯作者：
Blazer, Bruce R.
中科院分区：
文献类型：
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作者：
Saha, Asim;O'Connor, Roddy S.;Blazer, Bruce R.
程序性死亡配体-1 （PD-L1）与PD-1的相互作用诱导T细胞衰竭，是增强对癌症和慢性感染的免疫反应的治疗靶点。在小鼠骨髓移植模型中，宿主靶组织上PD-L1的表达降低了移植物抗宿主病（GVHD）的发生率。PD-L1也在T细胞上表达；然而，目前尚不清楚PD-L1是否会影响这些人群的免疫功能。在这里，我们研究了PD-L1对GVHD中T细胞功能的调节作用。在严重GVHD患者中，供体T细胞上PD-L1表达升高。与接受WT T细胞的小鼠相比，接受Pdl1（-/-）供体T细胞的小鼠GVHD降低。pd - l1缺陷T细胞肠道归巢受体的表达减少，炎症细胞因子的产生减少，细胞凋亡率增加。此外，多种生物能量途径，包括有氧糖酵解、氧化磷酸化和脂肪酸代谢，也在缺乏PD-L1的T细胞中减少。最后，在接受Pdl1（-/-）供体细胞的小鼠中，急性GVHD致死率的降低并不影响移植物抗白血病反应。这些数据表明，PD-L1选择性地增强T细胞介导的免疫应答，提示PD-1/PD-L1轴具有上下文依赖的功能，并提示PD-L1对供体T细胞的选择性抑制是预防或改善GVHD的潜在策略。
Programmed death ligand-1 (PD-L1) interaction with PD-1 induces T cell exhaustion and is a therapeutic target to enhance immune responses against cancer and chronic infections. In murine bone marrow transplant models, PD-L1 expression on host target tissues reduces the incidence of graft-versus-host disease (GVHD). PD-L1 is also expressed on T cells; however, it is unclear whether PD-L1 on this population influences immune function. Here, we examined the effects of PD-L1 modulation of T cell function in GVHD. In patients with severe GVHD, PD-L1 expression was increased on donor T cells. Compared with mice that received WT T cells, GVHD was reduced in animals that received T cells from Pdl1(-/-) donors. PD-L1-deficient T cells had reduced expression of gut homing receptors, diminished production of inflammatory cytokines, and enhanced rates of apoptosis. Moreover, multiple bioenergetic pathways, including aerobic glycolysis, oxidative phosphorylation, and fatty acid metabolism, were also reduced in T cells lacking PD-L1. Finally, the reduction of acute GVHD lethality in mice that received Pdl1(-/-) donor cells did not affect graft-versus-leukemia responses. These data demonstrate that PD-L1 selectively enhances T cell-mediated immune responses, suggesting a context-dependent function of the PD-1/PD-L1 axis, and suggest selective inhibition of PD-L1 on donor T cells as a potential strategy to prevent or ameliorate GVHD.