The altered PD-1/PD-L1 pathway delivers the ‘one-two punch’ effects to promote the Treg/Th17 imbalance in pre-eclampsia (original) (raw)
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Scientific Reports, 2016
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. However, the association between the PD-1/PD-L1 pathway and the Treg/Th17 imbalance has not been fully investigated in pre-eclampsia (PE). In this study, we observed an inverse correlation between the percentages of Treg and Th17 cells, and the expression of PD-1 and PD-L1 on the two subsets also changed in PE compared with normal pregnancy. We further explored their relationship in vivo using the L-NG-Nitroarginine Methyl Ester (L-NAME) induced PE-like rat models, also characterized by Treg/ Th17 imbalance. Administration of PD-L1-Fc protein provides a protective effects on the pre-eclamptic models, both to the mother and the fetuses, by reversing Treg/Th17 imbalance through inhibiting PI3K/ AKT/m-TOR signaling and enhancing PTEN expression. In addition, we also observed a protective effect of PD-L1-Fc on the placenta by reversing placental damages. These results suggested that altered PD-1/ PD-L1 pathway contributed to Treg/Th17 imbalance in PE. Treatment with PD-L1-Fc posed protective effects on pre-eclamptic models, indicating that the use of PD-L1-Fc might be a potential therapeutic target in PE treatment. Pre-eclampsia (PE) is a pregnancy-specific, immune-mediated syndrome affecting approximately 2-7% of pregnant women, a primary cause of maternal and perinatal mortality globally 1,2. Although efforts have been made, there is still a void in understanding its clear pathogenesis. Due to the life-threatening risk of PE and the lack of effective treatment, there is a pressing need for us to identify the key pathogenesis of PE and find effective treatment to protect both the mothers and babies. Balanced immune responses are essential for the maintenance of successful pregnancy 3. Aberrant responses of the immune system during pregnancy are suggested to play an important role in the pathogenesis of PE 4. Various immunological factors, such as activated monocytes and neutrophil, dysfunctional cytokines, T helper-1 predominance over Th2 cells and imbalance between regulatory T (Treg) and Th17 cells etc., have been reported in PE 5-8. Treg cells are a specialized subset of T 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) 9-11. Their absence impairs mice pregnancy, while the adoptive transfer of Treg cells, not only could rescue pregnancy in abortion-prone mice 12 , but also reduces IL-17 increased abortion rates in the CBA/J× BALB/c mouse model 13. Therefore, the balance between Treg and Th17 cells plays a critical role in the establishment of maternal-fetal tolerance and maintenance of pregnancy. Numerous studies proved that elevated levels of Treg cells are associated with NP 14 , while deficiencies in quantity and/or function of Treg cells and/or excessive Th17-immunity have been demonstrated in women suffering from PE 15-17. What contributes to a Treg/Th17 imbalance in PE has not been ascertained.
American Journal of Reproductive Immunology, 2009
Problem Regulatory T cells (Treg) play an important role in fetal protection. They expand during normal pregnancy and protect paternal/fetal antigens from rejection by maternal effector cells. Accordingly, the transfer of Treg obtained from BALB/c-mated CBA/J females prevents abortion in DBA/2J-mated animals. The actual mechanism through which Treg mediate their protective effect is still inconclusive. Cytotoxic T lymphocyte antigen-4 (CTLA-4) and Programmed cell death 1 (PD-1) are some of known Treg-associated molecules; however, their role in Treg-mediated fetal protection in murine model has not been investigated.Method of study Treg obtained from normal pregnant animals (NP; CBA/J × BALB/c) on day 14 were adoptively transferred into abortion-prone mice (AP; CBA/J × DBA/2J) intravenously on day 2 of pregnancy. An amount of 250 μg of either anti-PD-1 or anti-CTLA-4 mAb were injected intraperitoneally on days 0, 3, 6 and 9 of pregnancy. Controls received Treg + IgG or Treg + PBS. NP or AP treated with PBS served as additional controls.Results Blocking PD-1 abrogated the protective effect of Treg, resulting in a higher median abortion rate in comparison with the Treg/isotype-treated control while CTLA-4 blockage did not interfere with the protective effect of Treg. This was associated with a diminished number of vascular endothelial growth factor-A+ cells, previously reported as stimulators of lymphocyte extravasation in preterm labor.Conclusion Our data suggest PD-1 as an important mediator in Treg-induced fetal protection in the CBA/J × DBA/2J murine model.
Treg suppressive activity involves estrogen-dependent expression of programmed death-1 (PD-1)
International Immunology, 2007
Estrogen [17-b-estradiol (E2)] is a potent driver of the FoxP3+ regulatory T cell (Treg) compartment. Recently, Tregs were further characterized by intracellular expression of the negative co-stimulatory molecule, programmed death-1 (PD-1). To clarify the role of PD-1 versus FoxP3 in E2-enhanced Treg suppression, we evaluated both markers and functional suppression in wild-type, estrogen receptor knockout (ERKO) mice and PD-1 KO mice. We demonstrate that intracellular PD-1 expression is also E2 sensitive, since E2 treatment increased intracellular PD-1 levels in CD4+FoxP3+ cells, and PD-1 expression and Treg suppression were reduced in ERKO mice. Surprisingly, PD-1 KO mice retained normal levels of FoxP3 expression, but Tregs from these mice lacked functional suppression. However, E2 pre-treatment of PD-1 KO mice partially restored functional Treg suppression without enhancing FoxP3 expression. Thus, functional Treg suppression in immunized mice without E2 pretreatment was more closely linked to PD-1 expression than to FoxP3 expression. However, although enhanced PD-1 expression was E2 dependent, functional suppression was still enhanced by E2 pretreatment in the absence of PD-1. These data clearly demonstrate that E2 can affect multiple regulatory elements that influence Treg suppression, including both PD-1-dependent and PD-1independent pathways.
Annals of Translational Medicine, 2020
Tumor immunotherapy, especially that involving programmed cell death protein-1 (PD-1)/ programmed death-ligand 1 (PD-L1) immunosuppressive checkpoint inhibitors, has become an important part of tumor treatment strategy in the past decade. Blocking PD-1/PD-L1 signaling pathway can reduce the inhibitory effect of PD-1 pathway on T cells, promote the anti-tumor activity of activated T cells, and prolong the remission period of tumor. While PD-1/PD-L1 immunotherapy is effective in the treatment of solid malignant tumors, it also has shortcomings, due to the complexity of the tumor microenvironment (TME). Regulatory T cells (Tregs) and T helper 17 (Th17) cells play an important role in the TME and are closely related to the occurrence and development of tumors. Tregs can inhibit the anti-tumor immune effect, while Th17 cells play a dual role in tumor immunity, which not only promotes tumorigenesis but also promotes anti-tumor immunity. In the occurrence and development of tumor, PD-1/PD-L1 pathway, Tregs and Th17 cells are interrelated. However, the complicated relationship between the PD-1/PD-L1 pathway, Tregs, and Th17 cells has not been fully clarified. Here, we summarize the immunoregulation mechanisms and discuss the crosstalk between the PD-1/PD-L1 pathway, Tregs, and Th17 cells, with the aim of providing novel insights for future cancer treatment.
PD-1 is expressed by and regulates human group 3 innate lymphoid cells in human decidua
Mucosal Immunology, 2019
Group 3 innate lymphoid cells (ILC3) have been detected in both murine and human decidual tissues where they are thought to play a relevant role in the induction and maintenance of pregnancy. However, limited information exists on the molecular mechanisms that regulate these cells, including immune checkpoints. Here, we show that ILC3 express the inhibitory checkpoints programmed cell death (PD-1) and T cell immunoglobulin and mucin domain containing protein 3 (TIM-3) during the first trimester of pregnancy and that these receptors could regulate production of cytokines, including IL-22, IL-8, and TNF-α, induced by IL-23. We also show that the intermediate extravillous trophoblast (iEVT) expresses high levels of the PD-1-ligand PD-L1, suggesting that PD-1/PD-L1 interaction may regulate ILC3 function at the feto-maternal interface. Our present data provide the first evidence that human decidual ILC3 express a functional PD-1. It is possible that an altered expression or function of PD-1 may break the immunetolerance resulting in pregnancy failure.
Treg versus Th17 lymphocyte lineages are cross-regulated by LIF versus IL-6
Cell Cycle, 2009
Within the immune system there is an exquisite ability to discriminate between "self " and "non-self " that is orchestrated by T lymphocytes. Discriminatory pathways guide differentiation of these lymphocytes into either regulatory (Treg) or effector (Teff) T cells, influenced by cues from the naïve T cell's immediate micro-environment as it responds to cognate antigen. Reciprocal pathways may lead to commitment of naïve T cells into either the protective tolerance-promoting Treg, or to the pro-inflammatory Th17 effector phenotype. Primary activation of CD4 + lymphocytes stimulates their release of leukemia inhibitory factor (LIF), and Treg continue to release LIF in response to antigen, implying a role for LIF in tolerance. In contrast, interleukin-6 (IL-6), although very closely related to LIF, promotes maturation of Th17 cells. Here we show that LIF and IL-6 behave as polar opposites in promoting commitment to the Treg and Th17 lineages. Unlike IL6, LIF supported expression of Foxp3, the Treg lineage transcription factor, and LIF opposed IL6 by suppressing IL-6-induced IL-17A protein release. In striking contrast, we found that IL6 effectively inhibited LIF signalling, repressing transcription of the LIF receptor gp190, and strongly inducing axotrophin/MARCH-7, a novel E3 ubitquitin ligase that we discovered to be active in degradation of gp190 protein. In vivo, anti-LIF treatment reduced donorspecific Treg in recipients of foreign spleen cells. Conversely, a single dose of biodegradable LIF nanoparticles, targeted to CD4, successfully manipulated the LIF/IL6 axis towards development of donor-specific Foxp3 + Treg. The implications for therapy are profound, harnessing endogenous immune regulation by paracrine delivery of LIF to CD4 + cells in vivo.
The Journal of Immunology, 2009
CD4 ؉ CD25 high regulatory T cells (Tregs) are implicated in the maintenance of murine pregnancy. However, reports regarding circulating Treg frequencies in human pregnancy are inconsistent, and the functionality and phenotype of these cells in pregnancy have not been clarified. The aim of this study was to determine the frequency, phenotype, and function of circulating Tregs in the second trimester of human pregnancy and the influence of progesterone and 17-estradiol on Treg phenotype and frequency. Based on expressions of Foxp3, CD127, and HLA-DR as determined by multicolor flow cytometry, we defined a proper CD4 dim CD25 high Treg population and showed, in contrast to most previous reports, that this population was reduced in second trimester of pregnancy. Unexpectedly, Foxp3 expression was decreased in the Treg, as well as in the CD4 ؉ population. These changes could be replicated in an in vitro system resembling the pregnancy hormonal milieu, where 17-estradiol, and in particular progesterone, induced, in line with the pregnancy situation, a reduction of CD4 dim CD25 high Foxp3 ؉ cells in PBMC from nonpregnant women. By coculturing FACS-sorted Tregs and autologous CD4 ؉ CD25 ؊ responder cells, we showed that Tregs from pregnant women still displayed the same suppressive capacity as nonpregnant women in terms of suppressing IL-2, TNF-␣, and IFN-␥ secretion from responder cells while efficiently producing IL-4 and IL-10. Our findings support the view of hormones, particularly progesterone, as critical regulators of Tregs in pregnancy. Furthermore, we suggest that in the light of the results of this study, early data on circulating Treg frequencies in pregnancy need reevaluation.
The Journal of …, 2009
CD4 ؉ CD25 high regulatory T cells (Tregs) are implicated in the maintenance of murine pregnancy. However, reports regarding circulating Treg frequencies in human pregnancy are inconsistent, and the functionality and phenotype of these cells in pregnancy have not been clarified. The aim of this study was to determine the frequency, phenotype, and function of circulating Tregs in the second trimester of human pregnancy and the influence of progesterone and 17-estradiol on Treg phenotype and frequency. Based on expressions of Foxp3, CD127, and HLA-DR as determined by multicolor flow cytometry, we defined a proper CD4 dim CD25 high Treg population and showed, in contrast to most previous reports, that this population was reduced in second trimester of pregnancy. Unexpectedly, Foxp3 expression was decreased in the Treg, as well as in the CD4 ؉ population. These changes could be replicated in an in vitro system resembling the pregnancy hormonal milieu, where 17-estradiol, and in particular progesterone, induced, in line with the pregnancy situation, a reduction of CD4 dim CD25 high Foxp3 ؉ cells in PBMC from nonpregnant women. By coculturing FACS-sorted Tregs and autologous CD4 ؉ CD25 ؊ responder cells, we showed that Tregs from pregnant women still displayed the same suppressive capacity as nonpregnant women in terms of suppressing IL-2, TNF-␣, and IFN-␥ secretion from responder cells while efficiently producing IL-4 and IL-10. Our findings support the view of hormones, particularly progesterone, as critical regulators of Tregs in pregnancy. Furthermore, we suggest that in the light of the results of this study, early data on circulating Treg frequencies in pregnancy need reevaluation.
PD-1:PD-L inhibitory pathway affects both CD4+ and CD8+ T cells and is overcome by IL-2
European Journal of Immunology, 2002
Programmed death-1 (PD-1) is an immunoreceptor tyrosine-based inhibitory motif (ITIM)containing receptor expressed upon T cell activation. PD-1 -/animals develop autoimmune diseases, suggesting an inhibitory role for PD-1 in immune responses. Members of the B7 family, PD-L1 and PD-L2, are ligands for PD-1. This study examines the functional consequences of PD-1:PD-L engagement on murine CD4 and CD8 T cells and shows that these interactions result in inhibition of proliferation and cytokine production. T cells stimulated with anti-CD3/PD-L1.Fc-coated beads display dramatically decreased proliferation and IL-2 production, while CSFE analysis shows fewer cells cycling and a slower division rate. Costimulation with soluble anti-CD28 mAb can overcome PD-1-mediated inhibition by augmenting IL-2 production. However, PD-1:PD-L interactions inhibit IL-2 production even in the presence of costimulation and, thus, after prolonged activation, the PD-1:PD-L inhibitory pathway dominates. Exogenous IL-2 is able to overcome PD-L1-mediated inhibition at all times, indicating that cells maintain IL-2 responsiveness. Experiments using TCR transgenic CD4 + or CD8 + T cells stimulated with antigen-presenting cells expressing PD-L1 show that both T cell subsets are susceptible to this inhibitory pathway. However, CD8 + T cells may be more sensitive to modulation by the PD-1:PD-L pathway because of their intrinsic inability to produce significant levels of IL-2.