Family Planning Research Institute, Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China.
Cell Mol Immunol. 2018 Jul;15(7):710-723. doi: 10.1038/cmi.2017.70. Epub 2017 Sep 11.
The programmed cell death-1 (PD-1)/PD-ligand 1 (PD-L1) pathway is critical for normal pregnancy by promoting regulatory T (Treg) cell development and inhibiting the Th17 response. However, the relationship between the PD-1/PD-L1 pathway and the Treg/Th17 imbalance in pre-eclampsia (PE) is an enigma. In this study, decreased PD-1 and PD-L1 expression and a Treg/Th17 imbalance were observed at the maternal-fetal interface in PE. The regulatory effects of the PD-1/PD-L1 pathway on the Treg and Th17 cell quantities were determined in vitro by targeting T-cell proliferation, differentiation and transdifferentiation. First, decreased PD-1 expression might contribute to a higher Th17 cell frequency by promoting proliferation in PE. Second, the percentages of Treg but not Th17 cells differentiated from peripheral naive CD4 T cells were increased by PD-L1 Fc administration. This effect was accompanied by decreased PI3K/AKT/m-TOR and increased PTEN mRNA expression and was completely reversed by PD-1 blockade. Finally, the percentage of IL-17-producing Treg cells increased and was positively associated with the Th17 cell frequency in PE. Increased RORγt and IL-17 but not Foxp3 and IL-10 mRNA expression by Treg cells was observed with PD-1 blockade. Similar findings occurred when Treg cells were exposed to IL-6/IL-23/IL-1β and were reversed by PD-L1 Fc. Taken together, our findings indicate that the PD-1/PD-L1 pathway contributes to the Treg/Th17 imbalance via 'one-two punch' approaches: (i) promoting Th17 cell proliferation, (ii) inhibiting Treg cell differentiation and (iii) enhancing Treg cell plasticity into Th17 cells in PE. The therapeutic value of PD-L1 Fc for PE treatment will be explored in the future.
程序性细胞死亡受体 1（PD-1）/程序性细胞死亡配体 1（PD-L1）通路通过促进调节性 T（Treg）细胞的发育和抑制 Th17 反应，对正常妊娠至关重要。然而，PD-1/PD-L1 通路与子痫前期（PE）中 Treg/Th17 失衡的关系尚不清楚。在这项研究中，我们观察到 PE 患者母胎界面 PD-1 和 PD-L1 表达降低，Treg/Th17 失衡。通过靶向 T 细胞增殖、分化和转分化，在体外确定了 PD-1/PD-L1 通路对 Treg 和 Th17 细胞数量的调节作用。首先，PD-1 表达降低可能通过促进增殖导致较高的 Th17 细胞频率，从而导致 PE 中 Th17 细胞频率升高。其次，PD-L1 Fc 给药增加了外周幼稚 CD4 T 细胞分化而来的 Treg 细胞的比例，但不增加 Th17 细胞的比例。这种作用伴随着 PI3K/AKT/m-TOR 减少和 PTEN mRNA 表达增加，并且被 PD-1 阻断完全逆转。最后，PE 中产生 IL-17 的 Treg 细胞比例增加，与 Th17 细胞频率呈正相关。阻断 PD-1 可观察到 Treg 细胞中 RORγt 和 IL-17 但不是 Foxp3 和 IL-10 mRNA 表达增加。当 Treg 细胞暴露于 IL-6/IL-23/IL-1β 时，也观察到类似的结果，并且被 PD-L1 Fc 逆转。总之，我们的研究结果表明，PD-1/PD-L1 通路通过“双重打击”途径导致 Treg/Th17 失衡：（i）促进 Th17 细胞增殖，（ii）抑制 Treg 细胞分化，（iii）增强 Treg 细胞向 Th17 细胞的可塑性。未来将探索 PD-L1 Fc 治疗 PE 的治疗价值。
