The altered PD-1/PD-L1 pathway delivers the 'one-two punch' effects to promote the Treg/Th17 imbalance in pre-eclampsia. Issue 7 (July 2018)

• Record Type: Journal Article
• Authors: Zhang, Yonghong; Liu, Zhaozhao; Tian, Mei; Hu, Xiaohui; Wang, Liling; Ji, Jinlu; Liao, Aihua
• Is Part Of: Cellular & molecular immunology. Volume 15:Issue 7(2018)
• Page Start: 710
• Page End: 723
• Publication Date: 2018-07
• Subjects: differentiation -- proliferation -- Th17 cell -- transdifferentiation -- Treg cell; Immunology -- Periodicals; Cellular immunity -- Periodicals; Molecular biology -- Periodicals; 616.079
• DOI: 10.1038/cmi.2017.70
• Languages: English
• ISSNs: 1672-7681

Abstract

Abstract 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 determinedin 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.