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/P...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-1βand 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.展开更多
基金This study was supported by research grants from the National Natural Science Foundation of China(NO.81471475).
文摘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-1βand 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.
