Prevalence of genital Mycoplasma in pregnancies with shortened cervix.

OBJECTIVE: To determine whether colonisation with genital Mycoplasma species (spp.) in patients presenting with a shortened cervix before 34th week of pregnancy is associated with preterm birth. METHODS: The collection of this retrospective study consisted of 100 pregnant women who presented to a German Tertiary Perinatal Center between 2017 and 2020 due to a shortened cervix defined as a cervical length of 25 mm or shorter measured by transvaginal ultrasound before 34 weeks of gestation. At the time of admission, gestational age ranged from 18 + 4 to 33 + 3 weeks (+ days) of pregnancy. All patients underwent urine polymerase chain reaction (PCR) for genital Mycoplasma [Ureaplasma (U.) urealyticum, U. parvum, M. hominis or M. genitalium]. Patients who were tested positive underwent a therapy with macrolides (azithromycin or clarithromycin). RESULTS: 37% of the patients were positive for Ureaplasma spp., whereas 5% (5 patients) were Mycoplasma spp.-positive. All the latter were simultaneously colonised with Ureaplasma spp. Ureaplasma-positive patients were significantly younger than those who were tested negative. Median maternal age at examination was 30 years (a) versus 31a (p = 0.04). There was no difference between Ureaplasma-positive and -negative patients regarding median maternal body mass index (BMI) (kg/m2) (23.4 versus 22.3, p = 0.41), cervical length at admission (mm) (15 versus 17, p = 0.17), gestational age at examination (days, d) (198 versus 197, p = 0.97) or gestational age at birth (d) (250 versus 257, p = 0.33), respectively. Comparing U. parvum-positive and U. urealyticum-positive patients, there was some weak indication that U. parvum-positive patients may get a shortening of the cervix earlier in pregnancy, as the median gestational age at examination was 196d versus 215d (p = 0.06). Regarding Mycoplasma-positive and -negative patients, there was no difference in all examined parameters. CONCLUSIONS: Overall, one-third of all women in our study with a shortened cervix before 34th week of pregnancy were colonised with genital Mycoplasma spp. We were able to show that pregnant women, who were treated with antibiotics when tested positive for genital Mycoplasma, gave birth at the same gestational age as patients with a shortened cervix without detected Mycoplasma. This raises the question of whether routine testing and early antibiotic treatment should be established in prenatal care.

Unlaid Eggs: Ovarian Damage after Low-Dose Radiation.

The total body irradiation of lymphomas and co-irradiation in the treatment of adjacent solid tumors can lead to a reduced ovarian function, premature ovarian insufficiency, and menopause. A small number of studies has assessed the radiation-induced damage of primordial follicles in animal models and humans. Studies are emerging that evaluate radiation-induced damage to the surrounding ovarian tissue including stromal and immune cells. We reviewed basic laboratory work to assess the current state of knowledge and to establish an experimental setting for further studies in animals and humans. The experimental approaches were mostly performed using mouse models. Most studies relied on single doses as high as 1 Gy, which is considered to cause severe damage to the ovary. Changes in the ovarian reserve were related to the primordial follicle count, providing reproducible evidence that radiation with 1 Gy leads to a significant depletion. Radiation with 0.1 Gy mostly did not show an effect on the primordial follicles. Fewer data exist on the effects of radiation on the ovarian microenvironment including theca-interstitial, immune, endothelial, and smooth muscle cells. We concluded that a mouse model would provide the most reliable model to study the effects of low-dose radiation. Furthermore, both immunohistochemistry and fluorescence-activated cell sorting (FACS) analyses were valuable to analyze not only the germ cells but also the ovarian microenvironment.

The New Old CD8+ T Cells in the Immune Paradox of Pregnancy.

CD8+ T cells are the most frequent T cell population in the immune cell compartment at the feto-maternal interface. Due to their cytotoxic potential, the presence of CD8+ T cells in the immune privileged pregnant uterus has raised considerable interest. Here, we review our current understanding of CD8+ T cell biology in the uterus of pregnant women and discuss this knowledge in relation to a recently published immune cell Atlas of human decidua. We describe how the expansion of CD8+ T cells with an effector memory phenotype often presenting markers of exhaustion is critical for a successful pregnancy, and host defense towards pathogens. Moreover, we review new evidence on the presence of long-lasting immunological memory to former pregnancies and discuss its impact on prospective pregnancy outcomes. The formation of fetal-specific memory CD8+ T cell subests in the uterus, in particular of tissue resident, and stem cell memory cells requires further investigation, but promises interesting results to come. Advancing the knowledge of CD8+ T cell biology in the pregnant uterus will be pivotal for understanding not only tissue-specific immune tolerance but also the etiology of complications during pregnancy, thus enabling preventive or therapeutic interventions in the future.

Vertically transferred maternal immune cells promote neonatal immunity against early life infections.

During mammalian pregnancy, immune cells are vertically transferred from mother to fetus. The functional role of these maternal microchimeric cells (MMc) in the offspring is mostly unknown. Here we show a mouse model in which MMc numbers are either normal or low, which enables functional assessment of MMc. We report a functional role of MMc in promoting fetal immune development. MMc induces preferential differentiation of hematopoietic stem cells in fetal bone marrow towards monocytes within the myeloid compartment. Neonatal mice with higher numbers of MMc and monocytes show enhanced resilience against cytomegalovirus infection. Similarly, higher numbers of MMc in human cord blood are linked to a lower number of respiratory infections during the first year of life. Our data highlight the importance of MMc in promoting fetal immune development, potentially averting the threats caused by early life exposure to pathogens.

A prenatally disrupted airway epithelium orchestrates the fetal origin of asthma in mice.

BACKGROUND: Prenatal challenges such as maternal stress perception increase the risk and severity of asthma during childhood. However, insights into the trajectories and targets underlying the pathogenesis of prenatally triggered asthma are largely unknown. The developing lung and immune system may constitute such targets. OBJECTIVE: Here we have aimed to identify the differential sex-specific effects of prenatal challenges on lung function, immune response, and asthma severity in mice. METHODS: We generated bone marrow chimeric (BMC) mice harboring either prenatally stress-exposed lungs or a prenatally stress-exposed immune (hematopoietic) system and induced allergic asthma via ovalbumin. Next-generation sequencing (RNA sequencing) of lungs and assessment of airway epithelial barrier function in ovalbumin-sensitized control and prenatally stressed offspring was also performed. RESULTS: Profoundly enhanced airway hyperresponsiveness, inflammation, and fibrosis were exclusively present in female BMC mice with prenatally stress-exposed lungs. These effects were significantly perpetuated if both the lungs and the immune system had been exposed to prenatal stress. A prenatally stress-exposed immune system alone did not suffice to increase the severity of these asthma features. RNA sequencing analysis of lungs from prenatally stressed, non-BMC, ovalbumin-sensitized females unveiled a deregulated expression of genes involved in asthma pathogenesis, tissue remodeling, and tight junction formation. It was also possible to independently confirm a tight junction disruption. In line with this, we identified an altered perinatal and/or postnatal expression of genes involved in lung development along with an impaired alveolarization in female prenatally stressed mice. CONCLUSION: Here we have shown that the fetal origin of asthma is orchestrated by a disrupted airway epithelium and further perpetuated by a predisposed immune system.

Sex-specific epigenetic gene activation profiles are differentially modulated in human placentas affected by intrauterine growth restriction.

BACKGROUND: The purpose of this study was to investigate the sex specific expression of histone protein modifications responsible for rapid gene expression in IUGR placentas. PATIENTS AND METHODS: We screened for fetal sex-specific expression of the histone proteins H3K4me3 and H3K9ac in 23 IUGR and 40 control placentas via immunohistochemistry. The trophoblast-like cell line BeWo was used in order to analyze a potential effect of stimulation with prednisolone on H3K4me3 and H3K9ac in vitro. Calculating regression models with additional adjustment for potential confounders were used. RESULTS: A significantly decreased level of H3K4me3 was detectable in female syncytiotrophoblasts, whereas H3K9ac was reduced predominantly in male extravillous throphoblast (EVT). No association to the gestational age existed. CONCLUSION: Our data showed a reduced expression of the histone proteins H3K4me3 (female) and H3K9ac (male) in IUGR, furthermore elevated cortisol levels may lead to a sex-specific down-regulation of histone proteins in IUGR placentas.

Perinatal Gram-Positive Bacteria Exposure Elicits Distinct Cytokine Responses In Vitro.

During pregnancy, infections caused by the gram-positive bacteria Enterococcus faecalis (E. faecalis), Streptococcus agalacticae (S. agalacticae), and Staphylococcus aureus (S. aureus) are major reasons for preterm labor, neonatal prematurity, meningitis, or sepsis. Here, we propose cytokine responses to bacterial infections by the immature perinatal immune system as central players in the pathogenesis of preterm birth and neonatal sepsis. We aimed to close the gap in knowledge about such cytokine responses by stimulating freshly isolated umbilical blood mononuclear cells (UBMC) with lysates of E. faecalis, S. agalacticae, and S. aureus collected from pregnant women in preterm labor. Bacterial lysates and, principally, S. aureus and S. agalacticae distinctly triggered most of the eleven inflammatory, anti-inflammatory, TH1/TH2 cytokines, and chemokines quantified in UBMC culture media. Chemokines depicted the most robust induction. Among them, MIP-1ß was further enhanced in UBMC from female compered to male newborn infants. Due to its stability and high levels, we investigated the diagnostic value of IL-8. IL-8 was critically upregulated in cord blood of preterm neonates suffering from infections compared to gestational age-matched controls. Our results provide novel clues about perinatal immunity, underscoring a potential value of IL-8 for the timely detection of infections and suggesting that MIP-1ß constitutes an early determinant of sex-specific immunity, which may contribute, e.g., to male's vulnerability to preterm birth.

Decidual immune cells: Guardians of human pregnancies.

During human pregnancy, trophoblast cells, the main cellular component of the placenta, invade deeply into uterine blood vessels and the modified endometrium (decidua). Hence, the maternal immune system must adapt to it. A successful pregnancy requires the tolerance of genetically different (allogenic) cells while the mother's immune competence is maintained. This tolerance is ensured through multiple overlapping and occasionally redundant innate and adaptive immune mechanisms. The present article aims to provide a broad overview on uterine immune cell components and the phenotypical and functional changes that they experience during pregnancy. Particularly, we seek to highlight very recent findings in functional adaptations to pregnancy in immune cell populations encountered in the decidua. These adaptations not only ensure tolerance to allogenic trophoblast cells but also promote optimal placental and fetal growth, simultaneously endeavoring to maintain immune surveillance to provide defense against infections.

Sex-specific regulation of stress-induced fetal glucocorticoid surge by the mouse placenta.

Antenatal stress increases the prevalence of diseases in later life, which shows a strong sex-specific effect. However, the underlying mechanisms remain unknown. Maternal glucocorticoids can be elevated by stress and are potential candidates to mediate the effects of stress on the offspring sex-specifically. A comprehensive evaluation of dynamic maternal and placental mechanisms modulating fetal glucocorticoid exposure upon maternal stress was long overdue. Here, we addressed this gap in knowledge by investigating sex-specific responses to midgestational stress in mice. We observed increased levels of maternal corticosterone, the main glucocorticoid in rodents, along with higher corticosteroid-binding globulin levels at midgestation in C57Bl/6 dams exposed to sound stress. This resulted in elevated corticosterone in female fetuses, whereas male offspring were unaffected. We identified that increased placental expression of the glucocorticoid-inactivating enzyme 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2; Hsd11b2 gene) and ATP-binding cassette transporters, which mediate glucocorticoid efflux toward maternal circulation, protect male offspring from maternal glucocorticoid surges. We generated mice with an Hsd11b2 placental-specific disruption (Hsd11b2PKO) and observed moderately elevated corticosterone levels in offspring, along with increased body weight. Subsequently, we assessed downstream glucocorticoid receptors and observed a sex-specific differential modulation of placental Tsc22d3 expression, which encodes the glucocorticoid-induced leucine zipper protein in response to stress. Taken together, our observations highlight the existence of unique and well-orchestrated mechanisms that control glucocorticoid transfer, exposure, and metabolism in the mouse placenta, pinpointing toward the existence of sex-specific fetal glucocorticoid exposure windows during gestation in mice.

Impaired Progesterone-Responsiveness of CD11c+ Dendritic Cells Affects the Generation of CD4+ Regulatory T Cells and Is Associated With Intrauterine Growth Restriction in Mice.

Up to 10% of pregnancies in Western societies are affected by intrauterine growth restriction (IUGR). IUGR reduces short-term neonatal survival and impairs long-term health of the children. To date, the molecular mechanisms involved in the pathogenesis of IUGR are largely unknown, but the failure to mount an adequate endocrine and immune response during pregnancy has been proposed to facilitate the occurrence of IUGR. A cross talk between the pregnancy hormone progesterone and innate immune cell subsets such as dendritic cells (DCs) is vital to ensure adequate placentation and fetal growth. However, experimental strategies to pinpoint distinct immune cell subsets interacting with progesterone in vivo have long been limited. In the present study, we have overcome this limitation by generating a mouse line with a specific deletion of the progesterone receptor (PR) on CD11c+ DCs. We took advantage of the cre/loxP system and assessed reproductive outcome in Balb/c-mated C57Bl/6 PRflox/floxCD11ccre/wt females. Balb/c-mated C57Bl/6 PRwt/wtCD11ccre/wt females served as controls. In all dams, fetal growth and development, placental function and maternal immune and endocrine adaptation were evaluated at different gestational time points. We observed a significantly reduced fetal weight on gestational day 13.5 and 18.5 in PRflox/floxCD11ccre/wt females. While frequencies of uterine CD11c+ cells were similar in both groups, an increased frequency of co-stimulatory molecules was observed on DCs in PRflox/floxCD11ccre/wt mice, along with reduced frequencies of CD4+ FoxP3+ and CD8+ CD122+ regulatory T (Treg) cells. Placental histomorphology revealed a skew toward increased junctional zone at the expense of the labyrinth in implantations of PRflox/floxCD11ccre/wt females, accompanied by increased plasma progesterone concentrations. Our results support that DCs are highly responsive to progesterone, subsequently adapting to a tolerogenic phenotype. If such cross talk between progesterone and DCs is impaired, the generation of pregnancy-protective immune cells subsets such as CD4+ and CD8+ Treg cells is reduced, which is associated with poor placentation and IUGR in mice.

Steroids, Pregnancy and Fetal Development.

Maternal glucocorticoids critically rise during pregnancy reaching up to a 20-fold increase of mid-pregnancy concentrations. Concurrently, another steroid hormone, progesterone, increases. Progesterone, which shows structural similarities to glucocorticoids, can bind the intracellular glucocorticoid receptor, although with lower affinity. Progesterone is essential for the establishment and continuation of pregnancy and it is generally acknowledged to promote maternal immune tolerance to fetal alloantigens through a wealth of immunomodulatory mechanisms. Despite the potent immunomodulatory capacity of glucocorticoids, little is known about their role during pregnancy. Here we aim to compare general aspects of glucocorticoids and progesterone during pregnancy, including shared common steroidogenic pathways, plasma transporters, regulatory pathways, expression of receptors, and mechanisms of action in immune cells. It was recently acknowledged that progesterone receptors are not ubiquitously expressed on immune cells and that pivotal features of progesterone induced- maternal immune adaptations to pregnancy are mediated via the glucocorticoid receptor, including e.g., T regulatory cells expansion. We hypothesize that a tight equilibrium between progesterone and glucocorticoids is critically required and recapitulate evidence supporting that their disequilibrium underlie pregnancy complications. Such a disequilibrium can occur, e.g., after maternal stress perception, which triggers the release of glucocorticoids and impair progesterone secretion, resulting in intrauterine inflammation. These endocrine misbalance might be interconnected, as increase in glucocorticoid synthesis, e.g., upon stress, may occur in detriment of progesterone steroidogenesis, by depleting the common precursor pregnenolone. Abundant literature supports that progesterone deficiency underlies pregnancy complications in which immune tolerance is challenged. In these settings, it is largely yet undefined if and how glucocorticoids are affected. However, although progesterone immunomodulation during pregnancy appear to be chiefly mediated glucocorticoid receptors, excess glucocorticoids cannot compensate by progesterone deficiency, indicating that additional und still undercover mechanisms are at play.

Glucocorticoid receptor in T cells mediates protection from autoimmunity in pregnancy.

Pregnancy is one of the strongest inducers of immunological tolerance. Disease activity of many autoimmune diseases including multiple sclerosis (MS) is temporarily suppressed by pregnancy, but little is known about the underlying molecular mechanisms. Here, we investigated the endocrine regulation of conventional and regulatory T cells (Tregs) during reproduction. In vitro, we found the pregnancy hormone progesterone to robustly increase Treg frequencies via promiscuous binding to the glucocorticoid receptor (GR) in T cells. In vivo, T-cell-specific GR deletion in pregnant animals undergoing experimental autoimmune encephalomyelitis (EAE), the animal model of MS, resulted in a reduced Treg increase and a selective loss of pregnancy-induced protection, whereas reproductive success was unaffected. Our data imply that steroid hormones can shift the immunological balance in favor of Tregs via differential engagement of the GR in T cells. This newly defined mechanism confers protection from autoimmunity during pregnancy and represents a potential target for future therapy.

Antenatal endogenous and exogenous glucocorticoids and their impact on immune ontogeny and long-term immunity.

Endogenous levels of glucocorticoids rise during pregnancy to warrant development and maturation of the fetal organs close to birth. However, during most of the gestation, the fetus is protected from excessive biologically active endogenous glucocorticoids by placental and fetal expression of 11ß-hydroxysteroid dehydrogenase 2 (11ß-HSD2). Maternal stress, which may overwhelm placental 11ß-HSD2 activity with high glucocorticoid levels, or administration of synthetic glucocorticoids to improve the survival chances of the premature newborn, are associated to postnatal increased risk for immune diseases. Fetal exposure to excessive glucocorticoids may underlie this altered postnatal immunity. Here, we revise the role that placental and fetal 11ß-HSD2, fetal glucocorticoid exposure, and programming of the offspring's the hypothalamic-pituitary-adrenal (HPA) axis play on concerted steps in immune fetal development. We could identify gaps in knowledge about glucocorticoid-induced programming of immune diseases. Finally, based on current evidence about glucocorticoid and HPA axis-mediated immune regulation, we hypothesize on mechanisms that could drive the enhanced risk for atopies, infections, and type I diabetes in offspring that were prenatally exposed to glucocorticoids.

CD74-Downregulation of Placental Macrophage-Trophoblastic Interactions in Preeclampsia.

RATIONALE: We hypothesized that cluster of differentiation 74 (CD74) downregulation on placental macrophages, leading to altered macrophage-trophoblast interaction, is involved in preeclampsia. OBJECTIVE: Preeclamptic pregnancies feature hypertension, proteinuria, and placental anomalies. Feto-placental macrophages regulate villous trophoblast differentiation during placental development. Disturbance of this well-balanced regulation can lead to pathological pregnancies. METHODS AND RESULTS: We performed whole-genome expression analysis of placental tissue. CD74 was one of the most downregulated genes in placentas from preeclamptic women. By reverse transcriptase-polymerase chain reaction, we confirmed this finding in early-onset (<34 gestational week, n=26) and late-onset (≥34 gestational week, n=24) samples from preeclamptic women, compared with healthy pregnant controls (n=28). CD74 protein levels were analyzed by Western blot and flow cytometry. We identified placental macrophages to express CD74 by immunofluorescence, flow cytometry, and RT-PCR. CD74-positive macrophages were significantly reduced in preeclamptic placentas compared with controls. CD74-silenced macrophages showed that the adhesion molecules ALCAM, ICAM4, and Syndecan-2, as well as macrophage adhesion to trophoblasts were diminished. Naive and activated macrophages lacking CD74 showed a shift toward a proinflammatory signature with an increased secretion of tumor necrosis factor-α, chemokine (C-C motif) ligand 5, and monocyte chemotactic protein-1, when cocultured with trophoblasts compared with control macrophages. Trophoblasts stimulated by these factors express more CYP2J2, sFlt1, TNFα, and IL-8. CD74-knockout mice showed disturbed placental morphology, reduced junctional zone, smaller placentas, and impaired spiral artery remodeling with fetal growth restriction. CONCLUSIONS: CD74 downregulation in placental macrophages is present in preeclampsia. CD74 downregulation leads to altered macrophage activation toward a proinflammatory signature and a disturbed crosstalk with trophoblasts.

Identification of suitable reference genes in the mouse placenta.

INTRODUCTION: Quantitative real-time reverse transcription polymerase chain reaction (RT-qPCR) is a reliable tool to analyse gene expression profiles. The expression of housekeeping genes generally serves as a reference for mRNA amount, assuming that it remains stable under pathophysiological and experimental conditions. To date, an empirical validation of reference genes suitable for RT-qPCR-based studies in the mouse placenta is missing. METHODS: We used NormFinder and BestKeeper statistical software to analyse the expression stability of candidate housekeeping genes quantified by RT-qPCR in mouse placentas. RESULTS: Fifteen of 32 potential candidate housekeeping genes analysed on gestation day (gd) 16.5 in mouse placentas exhibited an optimal cycle threshold (Ct). Among them B2m, Polr2a, Ubc, and Ywhaz genes showed the highest expression stability in placentas from control, but also experimentally-challenged mice. These genes as well as the currently widely used housekeeping genes Hprt1, Actb, and Gapdh were selected for further quality assessments. We quantified the Ct values of these selected genes in placental samples obtained from wild-type or genetically engineered dams at different gds, or upon selected experimental interventions known to affect placental phenotype. Among all housekeeping genes analysed, Polr2a was the most stably expressed and its expression stability excelled in combination with Ubc. DISCUSSION: Polr2a, especially in combination with Ubc, can be proposed as highly suitable endogenous reference for gene expression analysis in mouse-derived placental tissue. Moreover, the validation of both genes as a stable reference gene in human placenta-derived tissue strengthens the translational relevance of RT-qPCR findings using mouse placenta.

Relaxin Treatment in an Ang-II-Based Transgenic Preeclamptic-Rat Model.

Relaxin is a peptide related to pregnancy that induces nitric oxide-related and gelatinase-related effects, allowing vasodilation and pregnancy-related adjustments permitting parturition to occur. Relaxin controls the hemodynamic and renovascular adaptive changes that occur during pregnancy. Interest has evolved regarding relaxin and a therapeutic principle in preeclampsia and heart failure. Preeclampsia is a pregnancy disorder, featuring hypertension, proteinuria and placental anomalies. We investigated relaxin in an established transgenic rat model of preeclampsia, where the phenotype is induced by angiotensin (Ang)-II production in mid pregnancy. We gave recombinant relaxin to preeclamtic rats at day 9 of gestation. Hypertension and proteinuria was not ameliorated after relaxin administration. Intrauterine growth retardation of the fetus was unaltered by relaxin. Heart-rate responses and relaxin levels documented drug effects. In this Ang-II-based model of preeclampsia, we could not show a salubrious effect on preeclampsia.

Differential mouse-strain specific expression of Junctional Adhesion Molecule (JAM)-B in placental structures.

The junctional adhesion molecule (JAM)-B, a member of the immunoglobulin superfamily, is involved in stabilization of interendothelial cell-cell contacts, formation of vascular tubes, homeostasis of stem cell niches and promotion of leukocyte adhesion and transmigration. In the human placenta, JAM-B protein is abundant and mRNA transcripts are enriched in first-trimester extravillous trophoblast in comparison to the villous trophoblast. We here aimed to elucidate the yet unexplored spatio-temporal expression of JAM-B in the mouse placenta. We investigated and semi-quantified JAM-B protein expression by immunohistochemistry in early post-implantation si tes and in mid- to late gestation placentae of various murine mating combinations. Surprisingly, the endothelium of the placental labyrinth was devoid of JAM-B expression. JAM-B was mainly present in spongiotrophoblast cells of the junctional zone, as well as in the fetal vessels of the chorionic plate, the umbilical cord and in maternal myometrial smooth muscle. We observed a strain-specific placental increase of JAM-B protein expression from mid- to late gestation in Balb/c-mated C57BL/6 females, which was absent in DBA/2J-mated Balb/c females. Due to the essential role of progesterone during gestation, we further assessed a possible modulation of JAM-B in mid-gestational placentae deficient in the progesterone receptor (Pgr(-/-)) and observed an increased expression of JAM-B in Pgr(-/-) placentae, compared to Pgr(+/+) tissue samples. We propose that JAM-B is an as yet underappreciated trophoblast lineage-specific protein, which is modulated via the progesterone receptor and shows unique strain-specific kinetics. Future work is needed to elucidate its possible contribution to placental processes necessary to ensuring its integrity, ultimately facilitating placental development and fetal growth.

Progesterone and HMOX-1 promote fetal growth by CD8+ T cell modulation.

Intrauterine growth restriction (IUGR) affects up to 10% of pregnancies in Western societies. IUGR is a strong predictor of reduced short-term neonatal survival and impairs long-term health in children. Placental insufficiency is often associated with IUGR; however, the molecular mechanisms involved in the pathogenesis of placental insufficiency and IUGR are largely unknown. Here, we developed a mouse model of fetal-growth restriction and placental insufficiency that is induced by a midgestational stress challenge. Compared with control animals, pregnant dams subjected to gestational stress exhibited reduced progesterone levels and placental heme oxygenase 1 (Hmox1) expression and increased methylation at distinct regions of the placental Hmox1 promoter. These stress-triggered changes were accompanied by an altered CD8+ T cell response, as evidenced by a reduction of tolerogenic CD8+CD122+ T cells and an increase of cytotoxic CD8+ T cells. Using progesterone receptor- or Hmox1-deficient mice, we identified progesterone as an upstream modulator of placental Hmox1 expression. Supplementation of progesterone or depletion of CD8+ T cells revealed that progesterone suppresses CD8+ T cell cytotoxicity, whereas the generation of CD8+CD122+ T cells is supported by Hmox1 and ameliorates fetal-growth restriction in Hmox1 deficiency. These observations in mice could promote the identification of pregnancies at risk for IUGR and the generation of clinical interventional strategies.