The altered PD-1/PD-L1 pathway delivers the 'one-two punch' effects to promote the Treg/Th17 imbalance in pre-eclampsia
The altered PD-1/PD-L1 pathway delivers the 'one-two punch' effects to promote the Treg/Th17 imbalance in pre-eclampsia
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改变的 PD-1/PD-L1 通路可产生“一击两拳”效应，促进先兆子痫中的 Treg/Th17 失衡
DOI：
10.1038/cmi.2017.70
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发表时间：
2018-07-01
影响因子：
24.1
通讯作者：
Liao, Aihua
中科院分区：
文献类型：
--
作者：
Zhang, Yonghong;Liu, Zhaozhao;Liao, Aihua
程序性细胞死亡-1(PD-1)/PD-配体1(PD-L1)通路通过促进调节性T细胞(Treg)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)Treg/Th17失衡之间的关系仍是个谜。在本研究中，在PE的母胎界面观察到PD-1和PD-L1表达降低以及Treg/Th17失衡。通过靶向T细胞的增殖、分化和转分化，体外检测PD-1/PD-L1通路对Treg和Th17细胞数量的调节作用。首先，PD-1表达减少可能通过促进PE的增殖而导致Th17细胞频率升高。第二，PD-L1 Fc能提高外周血中原始CD4(+)T细胞分化为Treg细胞的百分率，但不能提高Th17细胞的分化百分率。这种作用伴随着PI3K/AKT/m-TOR的降低和PTEN mRNA表达的增加，并被PD-1阻断完全逆转。最后，PE中产生IL-17的Treg细胞百分比增加，且与Th17细胞频率呈正相关。PD-1阻断后，Treg细胞的ROR-γt和IL-17表达增加，而Foxp3和IL-10的表达无明显变化。当Treg细胞暴露于IL-6/IL-23/IL-1β并被PD-L1 Fc逆转时，也有类似的结果。综上所述，我们的研究结果表明，PD-1/PD-L1途径通过“一击”途径促进Th17细胞的增殖，抑制Treg细胞的分化，增强Treg细胞向Th17细胞的可塑性，从而促进了PE患者Treg/Th17细胞的失衡。PD-L1FC在PE治疗中的应用价值有待于进一步探讨。
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 ROR gamma t 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-1 beta 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.