Xi Xia, Liu Jing-Mei, Guo Jun-Ying
Department of Paediatrics, Dongying People's Hospital, Dongying, China.
Department of Clinical Laboratory, Dongying People's Hospital, Dongying, China.
Int Arch Allergy Immunol. 2018;176(3-4):255-267. doi: 10.1159/000489338. Epub 2018 Jun 6.
The balance between T helper 17 (Th17) and regulatory T cells (Treg) is a new paradigm in asthma pathogenesis, but no therapeutic targets could modulate the Th17/Treg balance specifically for asthma. Since previous studies have shown the programmed cell death-1(PD-1)/PD-ligand 1 (PD-L1) pathway is critical to immune homeostasis in this disease, we hypothesized that the PD-1/PD-L1 pathway might be involved in the regulation of Treg/Th17 imbalance in asthmatic children.
The percentage of Treg and Th17 cells and the expression of PD-1 and PD-L1 were detected by flow cytometry in children with asthma and healthy controls. CD4+ T cells were stimulated with Th17 and Treg differentiating factors, and treated with anti-PD-1. Then cells were harvested and measured for Th17 and Treg percentages and Foxp3 and RORγt levels using RT-PCR.
We observed an inverse correlation between the percentages of Treg and Th17 cells, and the expression of PD-1 and PD-L1 in the two subsets also changed in the mild persistent and moderate to severe persistent groups compared with healthy controls. In vitro, administration of anti-PD-1 could decrease Th17 percentages and RORγt mRNA, and increase Treg percentages and Foxp3 mRNA in CD4+ T cells of children with asthma in the mild persistent and moderate to persistent groups. Additionally, the role played by anti-PD-1 in regulating Treg/Th17 balance was further confirmed in an asthmatic mouse model.
Alteration of the PD-1/PD-L1 pathway can modulate Treg/Th17 balance in asthmatic children. Treatment with anti-PD-1 posed protective effects on asthma models, providing a novel theoretical target for asthma.
辅助性T细胞17（Th17）与调节性T细胞（Treg）之间的平衡是哮喘发病机制中的一个新范例，但尚无治疗靶点能够特异性调节哮喘的Th17/Treg平衡。由于先前的研究表明程序性细胞死亡蛋白1（PD-1）/PD配体1（PD-L1）通路对该疾病的免疫稳态至关重要，我们推测PD-1/PD-L1通路可能参与调节哮喘患儿的Treg/Th17失衡。
采用流式细胞术检测哮喘患儿和健康对照者中Treg和Th17细胞的百分比以及PD-1和PD-L1的表达。用Th17和Treg分化因子刺激CD4+T细胞，并用抗PD-1进行处理。然后收集细胞，使用逆转录聚合酶链反应（RT-PCR）检测Th17和Treg的百分比以及叉头框蛋白3（Foxp3）和维甲酸相关孤儿受体γt（RORγt）水平。
我们观察到Treg和Th17细胞百分比之间呈负相关，与健康对照相比，轻度持续性和中度至重度持续性组中这两个亚群的PD-1和PD-L1表达也发生了变化。在体外，给予抗PD-1可降低轻度持续性和中度至持续性哮喘患儿CD4+T细胞中的Th17百分比和RORγt信使核糖核酸（mRNA），并增加Treg百分比和Foxp3 mRNA。此外，在哮喘小鼠模型中进一步证实了抗PD-1在调节Treg/Th17平衡中的作用。
PD-1/PD-L1通路的改变可调节哮喘患儿的Treg/Th17平衡。抗PD-1治疗对哮喘模型具有保护作用，为哮喘提供了一个新的理论靶点。
