The programmed cell death-1(PD-1)/PD-ligand 1 (PD-L1) pathway is critical to immune homeostasis by promoting regulatory T (Treg) development and inhibiting effector T (such as Th17) cell responses. treatment. Pre-eclampsia (PE) is usually a pregnancy-specific, immune-mediated syndrome affecting approximately 2C7% of pregnant women, a main cause of maternal and perinatal mortality globally1,2. Although efforts have been made, there is usually still a void in understanding its obvious pathogenesis. Due to the life-threatening risk of PE and the lack of effective treatment, there is usually a pressing need for us to identify the important pathogenesis of PE and find effective treatment to safeguard both the mothers and babies. Balanced immune responses are essential for the maintenance of successful pregnancy3. Aberrant responses of the immune system during pregnancy are suggested to play an important role in the pathogenesis of PE4. Numerous immunological factors, such as Rabbit Polyclonal to BRI3B activated monocytes and neutrophil, dysfunctional cytokines, T helper Vatalanib -1 pre-dominance over Th2 cells and imbalance between regulatory T (Treg) and Th17 cells etc., have been reported in PE5,6,7,8. Treg cells are a specialized subset of T Vatalanib cells, with the suppressive capacity and regulatory function, playing an important role in the induction of maternal tolerance to the fetus and the maintenance of normal pregnancy (NP)9,10,11. Their absence impairs mice pregnancy, while the adoptive transfer of Treg cells, not only could rescue pregnancy in abortion-prone mice12, but also reduces IL-17 increased abortion rates in the CBA/J BALB/c mouse model13. Therefore, the balance between Treg and Th17 cells plays a crucial role in the organization of maternal-fetal tolerance and maintenance of pregnancy. Numerous studies proved that elevated levels of Treg cells are associated with NP14, while deficiencies in quantity and/or function of Treg cells and/or excessive Th17-immunity have been exhibited in women suffering from PE15,16,17. What contributes to a Treg/Th17 imbalance in PE has not been ascertained. The conversation between programmed cell death-1 (PD-1 or CD279) and its ligand (PD-L1 or CD274) has emerged as a important player in regulating immune response and peripheral tolerance18,19,20. The PD-1/PD-L1 pathway defends against potentially pathogenic effector T cells by simultaneously harnessing two mechanisms of peripheral tolerance: (I) promoting Treg development and function and (II) directly inhibiting pathogenic effector T cells20. PD-1-deficient mice developed spontaneous autoimmunity diseases, such as arthritis, lupus-like glomerulonephritis and cardiomyopathy21,22,23. Engagement of PD-1 with PD-L1 negatively regulates Th17 cells, which play pathogenic functions in the development of autoimmune diseases and graft-versus-host disease (GVHD)24,25. Apart from autoimmune disorders, this pathway has been confirmed to be involved in the organization of maternal-fetal tolerance26,27, since PD-L1 blockade results in the reduction in litter size, number and increase in embryo resorption of mice, and the failure of fetalCmaternal tolerance with Treg deficiency and hyperactivity of Th17 cells28. Therefore, the altered PD-1/PD-L1 pathway may be associated with the Treg/Th17 imbalance in human pregnancy29,30. The PD-1/PD-L1 pathway is usually considered a particularly attractive therapeutic target in autoimmune diseases, because the development of PD-1 agonists could deliver the necessary one-two strike to safeguard against self-reactivity: (I) augmenting iTreg function and (II) concomitantly suppressing the growth and functions of activated effector T cells20. Administration of soluble PD-L1-Fc protein has been reported to diminish the severity of collagen-induced arthritis and T-cell induced chronic colitis Vatalanib in the mouse model and to prevent cell proliferation and production of IL-17 and IL-23 by splenocytes24,31,32. Decreased Treg figures and increased Th17 activation are associated with PE. However, whether the PD-1/PD-L1 pathway is usually of relevance for Treg/Th17 imbalance in PE has not been discovered and is usually the main aim of our study. Results The Treg/Th17 imbalance and altered PD-1 and PD-L1 manifestation on the two subsets were observed in women with PE Our first objective was to characterize the percentages of circulating Treg cells and Th17 cells in blood samples from women with NP and women with PE (Table 1). Treg cells and Th17 cells were defined as CD4+ CD25brightCD127low/? and CD4+ IL-17A+, respectively. Gating strategies for Treg cells and Th17 cells were shown in Fig. 1A,W. The percentages of each subpopulation were decided by the proportion of either among CD4+ T cells. We observed an inverse correlation between the percentages of Treg and Th17 cells in NP versus PE. In PE, the percentage of Treg cells significantly decreased (generation of CD4+ Foxp3+ Treg cells from na?ve CD4+ T cells44. Moreover, PD-L1-Fc also enhances Foxp3 manifestation and suppresses function of established Treg cells44. In mechanistic studies, it has.