Cytokines, NK cells and regulatory T cell functions in normal pregnancy and reproductive failures.
American journal of reproductive immunology (New York, N.Y. : 1989)
PURPOSE OF THE REVIEW:Pregnancy brings about an intricate assortment of dynamic changes, which causes proper connection of genetically discordant maternal and foetal tissues. Uterine NK cells are immune cells populating the endometrium and play a major role in implantation and also regulate placentation. This review mainly aims explore the role of uterine NK cells in implantation and how it is affecting in adverse pregnancy outcomes. RECENT FINDINGS:Though the functions of uterine NK (uNK) cells are not clearly understood, NK cell activity plays a vital role during immunomodulation which is the main step in implantation and sustaining the early pregnancy. Cytokines, cell surface receptors of NK cells and hormones such as progesterone modulate the NK cell activity in turn affect the implantation of the embryo. Altered NK cell activity (number and functionality) would be an important attributing factor in adverse pregnancy outcomes. Furthermore, T regulatory cells and cytokines also modulate the immune responses in the decidua which in turn contributes to successful implantation of embryos. SUMMARY:Immunological responses and interactions in the Foetus-maternal interface is crucial in the successful implantation of allogenic foetus resulting in a healthy pregnancy. NK cells, Treg cells and cytokines play a major role in successful implantation which remains an enigma. Comprehending pregnancy-induced immunological changes at the foetus-maternal interface will allow newer therapeutic strategies to improve pregnancy outcomes.
10.1111/aji.13667
Progesterone Decreases in vitro Indoleamine 2, 3-dioxygenase Expression in Dendritic and CD4 Cells from Maternal-Fetal Interface of Rats.
Bianchi Pedro Kastein Faria da Cunha,Leandro Rafael Magdanelo,Poscai Aline Nayara,Yoshinaga Tulio,Gonçalez Patrícia Orlandini,Kfoury Junior José Roberto
Immunological investigations
PROBLEM:Several mechanisms contribute to the tolerogenic state observed during pregnancy, such as the activity of the enzyme indoleamine 2, 3-dioxygenase (IDO). This initializes the catabolism of tryptophan, inducing T cells to apoptosis due to its deprivation and by the action of its catabolites in the placental microenvironment. Progesterone plays an important part on immunological tolerance mechanisms during pregnancy; however, there is no evidence it is related to IDO activity. Thus, this study aimed to investigate progesterone influence on the maternal-fetal interface of pregnant Wistar rats, by identifying IDO positive cells by immunophenotyping and flow cytometry under exogenous progesterone supplementation. METHOD OF STUDY:Placenta and embryo cells were cultured and separated into groups that received interferon γ or progesterone, supplemented or not with mifepristone. After 2 and 24 h, these were labeled with an anti-IDO and a series of antibodies specific to leucocytes and progesterone receptor and processed through flow cytometry analysis. RESULTS:Progesterone induced a significant decrease in the expression of IDO in dendritic cells and CD4 lymphocytes. CONCLUSION:The blocking of progesterone receptor on these cells by mifepristone restored IDO expression levels and may constitute evidence of the participation of this hormone through a direct route in these cells.
10.1080/08820139.2017.1296856
A Potential Role and Contribution of Androgens in Placental Development and Pregnancy.
Parsons Agata M,Bouma Gerrit J
Life (Basel, Switzerland)
Successful pregnancy requires the establishment of a highly regulated maternal-fetal environment. This is achieved through the harmonious regulation of steroid hormones, which modulate both maternal and fetal physiology, and are critical for pregnancy maintenance. Defects in steroidogenesis and steroid signaling can lead to pregnancy disorders or even fetal loss. The placenta is a multifunctional, transitory organ which develops at the maternal-fetal interface, and supports fetal development through endocrine signaling, the transport of nutrients and gas exchange. The placenta has the ability to adapt to adverse environments, including hormonal variations, trying to support fetal development. However, if placental function is impaired, or its capacity to adapt is exceeded, fetal development will be compromised. The goal of this review is to explore the relevance of androgens and androgen signaling during pregnancy, specifically in placental development and function. Often considered a mere precursor to placental estrogen synthesis, the placenta in fact secretes androgens throughout pregnancy, and not only contains the androgen steroid nuclear receptor, but also non-genomic membrane receptors for androgens, suggesting a role of androgen signaling in placental function. Moreover, a number of pregnancy disorders, including pre-eclampsia, gestational diabetes, intrauterine growth restriction, and polycystic ovarian syndrome, are associated with abnormal androgen levels and androgen signaling. Understanding the role of androgens in the placenta will provide a greater understanding of the pathophysiology of pregnancy disorders associated with androgen elevation and its consequences.
10.3390/life11070644
Immunomodulatory role of decidual prolactin on the human fetal membranes and placenta.
Frontiers in immunology
The close interaction between fetal and maternal cells during pregnancy requires multiple immune-endocrine mechanisms to provide the fetus with a tolerogenic environment and protection against any infectious challenge. The fetal membranes and placenta create a hyperprolactinemic milieu in which prolactin (PRL) synthesized by the maternal decidua is transported through the amnion-chorion and accumulated into the amniotic cavity, where the fetus is bedded in high concentrations during pregnancy. PRL is a pleiotropic immune-neuroendocrine hormone with multiple immunomodulatory functions mainly related to reproduction. However, the biological role of PRL at the maternal-fetal interface has yet to be fully elucidated. In this review, we have summarized the current information on the multiple effects of PRL, focusing on its immunological effects and biological significance for the immune privilege of the maternal-fetal interface.
10.3389/fimmu.2023.1212736
Progesterone modulates CD4 CD25 FoxP3 regulatory T Cells and TGF-β1 in the maternal-fetal interface of the late pregnant mouse.
American journal of reproductive immunology (New York, N.Y. : 1989)
OBJECTIVE:Progesterone supplementation is recommended to prevent spontaneous preterm birth (sPTB) in clinical practice. However, the exact mechanism is still unclear. This study aims to better understand the mechanisms that progesterone can prevent PTB. METHODS:Late pregnant mice were given various doses of progesterone receptor antagonist mifepristone, and pregnancy outcomes were observed. Then, non-pregnant and pregnant mice were given a subcutaneous injection of 40 mg/kg progesterone and 5 mg/kg mifepristone, respectively. CD4 CD25 FoxP3 Treg cells in peripheral blood and decidua basalis were detected by FACS. Expressions of FoxP3 and TGF-β1 in the decidua basalis were detected. RESULTS:Mifepristone induced preterm birth, and an obvious dose-response was found. Proportions of CD4 CD25 FoxP3 Treg cells in the peripheral blood of non-pregnant mice increased significantly after progesterone injection. CD4 CD25 FoxP3 Treg cells in the peripheral blood of pregnant mice increased significantly compared with those of non-pregnant mice. In pregnant mice, mifepristone significantly decreased the proportions of CD4 CD25 FoxP3 Treg cells in peripheral blood, and reduced proportions of Treg cells at the maternal-fetal interface and expressions of FoxP3 and TGF-β1 in the maternal-fetal interface. Total 40 mg/kg of progesterone did not increase CD4 CD25 FoxP3 Treg in the peripheral blood of pregnant mice, but increased proportions of Treg cells at the maternal-fetal interface and up-regulated FoxP3 and TGF-β1 expressions in the maternal-fetal interface. CONCLUSION:Progesterone promotes pregnancy immune homeostasis by up-regulating Treg cells and TGF-β1 expression in the maternal-fetal interface. It may be one of the mechanisms of progesterone in preventing sPTB.
10.1111/aji.13541
Kisspeptin Is Upregulated at the Maternal-Fetal Interface of the Preeclamptic-like BPH/5 Mouse and Normalized after Synchronization of Sex Steroid Hormones.
Reproductive medicine (Basel, Switzerland)
Insufficient invasion of conceptus-derived trophoblast cells in the maternal decidua is a key event in the development of early-onset preeclampsia (PE), a subtype of PE associated with high maternal and fetal morbidity and mortality. Kisspeptins, a family of peptides previously shown to inhibit trophoblast cell invasion, have been implicated in the pathogenesis of early-onset PE. However, a role of kisspeptin signaling during the genesis of this syndrome has not been elucidated. Herein, we used the preeclamptic-like BPH/5 mouse model to investigate kisspeptin expression and potential upstream regulatory mechanisms in a PE-like syndrome. Expression of the kisspeptin encoding gene, , and the 10-amino-acid kisspeptide (Kp-10), are upregulated in the non-pregnant uterus of BPH/5 females during diestrus and in the maternal-fetal interface during embryonic implantation and decidualization. Correspondingly, the dysregulation of molecular pathways downstream to kisspeptins also occurs in this mouse model. BPH/5 females have abnormal sex steroid hormone profiles during early gestation. In this study, the normalization of circulating concentrations of 17β-estradiol (E2) and progesterone (P4) in pregnant BPH/5 females not only mitigated upregulation, but also rescued the expression of multiple molecules downstream to kisspeptin and ameliorated adverse fetoplacental outcomes. Those findings suggest that uterine upregulation occurs pre-pregnancy and persists during early gestation in a PE-like mouse model. Moreover, this study highlights the role of sex steroid hormones in uteroplacental dysregulation and the improvement of placentation by normalization of E2, P4 and .
10.3390/reprodmed3040021
The effects of progesterone on immune cellular function at the maternal-fetal interface and in maternal circulation.
The Journal of steroid biochemistry and molecular biology
Progesterone is a sex steroid hormone that plays a critical role in the establishment and maintenance of pregnancy. This hormone drives numerous maternal physiological adaptations to ensure the continuation of pregnancy and to facilitate fetal growth, including broad and potent modulation of the maternal immune system to promote maternal-fetal tolerance. In this brief review, we provide an overview of the immunomodulatory functions of progesterone in the decidua, placenta, myometrium, and maternal circulation during pregnancy. Specifically, we summarize current evidence of the regulated functions of innate and adaptive immune cells induced by progesterone and its downstream effector molecules in these compartments, including observations in human pregnancy and in animal models. Our review highlights the gaps in knowledge of interactions between progesterone and maternal cellular immunity that may direct future research.
10.1016/j.jsbmb.2023.106254
Progesterone-mediated remodeling of the maternal-fetal interface by a PGRMC1-dependent mechanism.
Journal of reproductive immunology
Implantation and maintenance of pregnancy involve intricate immunological processes that enable the developing fetus to coexist with the maternal immune system. Progesterone, a critical hormone during pregnancy, is known to promote immune tolerance and prevent preterm labor. However, the mechanism by which progesterone mediates these effects remains unclear. In this study, we investigated the role of the non-classical progesterone receptor membrane component 1 (PGRMC1) in progesterone signaling at the maternal-fetal interface. Using JEG3 cells, a trophoblast model cell line, we observed that progesterone stimulation increased the expression of human leukocyte antigen-C (HLA-C) and HLA-G, key molecules involved in immune tolerance. We also found that progesterone upregulated the expression of the transcription factor ELF3, which is known to regulate trophoblast-specific HLA-C expression. Interestingly, JEG3 cells lacked expression of classical progesterone receptors (PRs) but exhibited high expression of PGRMC1, a finding we confirmed in primary trophoblasts by mining sc-RNA seq data from human placenta. To investigate the role of PGRMC1 in progesterone signaling, we used CRISPR/Cas9 technology to knockout PGRMC1 in JEG3 cells. PGRMC1-deficient cells showed a diminished response to progesterone stimulation. Furthermore, we found that the progesterone antagonist RU486 inhibited ELF3 expression in a PGRMC1-dependent manner, suggesting that RU486 acts as a progesterone antagonist by competing for receptor binding. Additionally, we found that RU486 inhibited cell invasion, an important process for successful pregnancy, and this inhibitory effect was dependent on PGRMC1. Our findings highlight the crucial role of PGRMC1 in mediating the immunoregulatory effects of progesterone at the maternal-fetal interface.
10.1016/j.jri.2024.104244
Progestogen-driven B7-H4 contributes to onco-fetal immune tolerance.
Cell
Immune tolerance mechanisms are shared in cancer and pregnancy. Through cross-analyzing single-cell RNA-sequencing data from multiple human cancer types and the maternal-fetal interface, we found B7-H4 (VTCN1) is an onco-fetal immune tolerance checkpoint. We showed that genetic deficiency of B7-H4 resulted in immune activation and fetal resorption in allogeneic pregnancy models. Analogously, B7-H4 contributed to MPA/DMBA-induced breast cancer progression, accompanied by CD8 T cell exhaustion. Female hormone screening revealed that progesterone stimulated B7-H4 expression in placental and breast cancer cells. Mechanistically, progesterone receptor (PR) bound to a newly identified -58 kb enhancer, thereby mediating B7-H4 transcription via the PR-P300-BRD4 axis. PR antagonist or BRD4 degrader potentiated immunotherapy in a murine B7-H4 breast cancer model. Thus, our work unravels a mechanistic and biological connection of a female sex hormone (progesterone) to onco-fetal immune tolerance via B7-H4 and suggests that the PR-P300-BRD4 axis is targetable for treating B7-H4 cancer.
10.1016/j.cell.2024.06.012
Cytokines, Hormones and Cellular Regulatory Mechanisms Favoring Successful Reproduction.
Piccinni Marie-Pierre,Raghupathy Raj,Saito Shigeru,Szekeres-Bartho Julia
Frontiers in immunology
Its semi-allogeneic nature renders the conceptus vulnerable to attack by the maternal immune system. Several protective mechanisms operate during gestation to correct the harmful effects of anti-fetal immunity and to support a healthy pregnancy outcome. Pregnancy is characterized by gross alterations in endocrine functions. Progesterone is indispensable for pregnancy and humans, and it affects immune functions both directly and mediators. The progesterone-induced mediator - PIBF - acts in favor of Th2-type immunity, by increasing Th2 type cytokines production. Except for implantation and parturition, pregnancy is characterized by a Th2-dominant cytokine pattern. Progesterone and the orally-administered progestogen dydrogesterone upregulate the production of Th2-type cytokines and suppress the production of Th1 and Th17 cytokine production . This is particularly relevant to the fact that the Th1-type cytokines TNF-α and IFN-γ and the Th17 cytokine IL-17 have embryotoxic and anti-trophoblast activities. These cytokine-modulating effects and the PIBF-inducing capabilities of dydrogesterone may contribute to the demonstrated beneficial effects of dydrogesterone in recurrent spontaneous miscarriage and threatened miscarriage. IL-17 and IL-22 produced by T helper cells are involved in allograft rejection, and therefore could account for the rejection of paternal HLA-C-expressing trophoblast. Th17 cells (producing IL-17 and IL-22) and Th22 cells (producing IL-22) exhibit plasticity and could produce IL-22 and IL-17 in association with Th2-type cytokines or with Th1-type cytokines. IL-17 and IL-22 producing Th cells are not harmful for the conceptus, if they also produce IL-4. Another important protective mechanism is connected with the expansion and action of regulatory T cells, which play a major role in the induction of tolerance both in pregnant women and in tumour-bearing patients. Clonally-expanded Treg cells increase at the feto-maternal interface and in tumour-infiltrating regions. While in cancer patients, clonally-expanded Treg cells are present in peripheral blood, they are scarce in pregnancy blood, suggesting that fetal antigen-specific tolerance is restricted to the foeto-maternal interface. The significance of Treg cells in maintaining a normal materno-foetal interaction is underlined by the fact that miscarriage is characterized by a decreased number of total effector Treg cells, and the number of clonally-expanded effector Treg cells is markedly reduced in preeclampsia. In this review we present an overview of the above mechanisms, attempt to show how they are connected, how they operate during normal gestation and how their failure might lead to pregnancy pathologies.
10.3389/fimmu.2021.717808