Feto-maternal Immune Tolerance Research Articles

Immune Checkpoint Inhibitors and Pregnancy: Analysis of the VigiBase® Spontaneous Reporting System.

In pregnancy, immune checkpoint pathways are involved in the maintenance of fetomaternal immune tolerance. Preclinical studies have shown that immune checkpoint inhibitors (ICIs) increase the risk of fetal death. Despite the fact that using ICIs in pregnant women and women of childbearing potential is not recommended, some case reports of ICI exposure in pregnancy have been published showing favorable fetal outcomes. This study aimed to gain further insight into ICI safety in pregnancy by querying VigiBase®, the World Health Organization's spontaneous reporting system. We performed raw and subgroup disproportionality analyses using the reporting odds ratio and comparing ICIs with the entire database, other antineoplastic agents, and other antineoplastic agents gathered in VigiBase® since 2011. Across 103 safety reports referring to ICI exposure during the peri-pregnancy period, 56 reported pregnancy-related outcomes, of which 46 were without concomitant drugs as potential confounding factors. No signals of disproportionate reporting were found for spontaneous abortion, fetal growth restriction, and prematurity. In light of the expanding indications of ICIs, continuous surveillance by clinicians and pharmacovigilance experts is warranted, along with pharmacoepidemiological studies on other sources of real-world evidence, such as birth records, to precisely assess ICI exposure during the peri-pregnancy period and further characterize relevant outcomes.

Galectins in Early Pregnancy and Pregnancy-Associated Pathologies.

Galectins are a family of conserved soluble proteins defined by an affinity for β-galactoside structures present on various glycoconjugates. Over the past few decades, galectins have been recognized as important factors for successful implantation and maintenance of pregnancy. An increasing number of studies have demonstrated their involvement in trophoblast cell function and placental development. In addition, several lines of evidence suggest their important roles in feto-maternal immune tolerance regulation and angiogenesis. Changed or dysregulated galectin expression is also described in pregnancy-related disorders. Although the data regarding galectins’ clinical relevance are still at an early stage, evidence suggests that some galectin family members are promising candidates for better understanding pregnancy-related pathologies, as well as predicting biomarkers. In this review, we aim to summarize current knowledge of galectins in early pregnancy as well as in pregnancy-related pathologies.

Tumor-derived GDF-15 to suppress t-lymphocyte recruitment to the tumor microenvironment resulting in resistance to ANTI-PD-1 treatment.

e14532 Background: Growth and differentiation factor 15 (GDF-15) is a divergent member of the TGF-β superfamily with low to absent expression in healthy tissue. GDF-15 has been linked to feto-maternal immune tolerance, to prevention of excessive immune cell infiltration during tissue damage, and to anorexia. Various major tumor types secrete high levels of GDF-15. In cancer patients, elevated GDF-15 serum levels correlate with poor prognosis and reduced overall survival (OS). Methods: Impact of a proprietary GDF-15 neutralizing antibody (CTL-002) regarding T cell trafficking was analyzed by whole blood adhesion assays, a HV18-MK melanoma-bearing humanized mouse model and a GDF-15-transgenic MC38 model. Additionally, patient GDF-15 serum levels were correlated with clinical response and overall survival in oropharyngeal squamous cell carcinoma (OPSCC) and melanoma brain metastases. Results: In whole blood cell adhesion assays GDF-15 impairs adhesion of T and NK cells to activated endothelial cells. Neutralization of GDF-15 by CTL-002 rescued T cell adhesion. In HV18-MK-bearing humanized mice CTL-002 induced a strong increase in TIL numbers. Subset analysis revealed an overproportional enrichment of T cells, in particular CD8+ T cells. As immune cell exclusion is detrimental for checkpoint inhibitor (CPI) therapy, a GDF-15-transgenic MC38 model was tested for anti-PD-1 therapy efficacy. In GDF-15 overexpressing MC38 tumors response to anti PD-1 therapy was reduced by 90% compared to wtMC38 tumors. Combining aPD-1 with CTL-002 resulted in 50% of the mice rejecting their GDF-15 overexpressing tumors. Clinically, inverse correlations of GDF-15 levels with CD8+ T cell infiltration were shown for HPV+ OPSCC and for melanoma brain metastases. GDF-15 serum levels were significantly higher in HPV- than in HPV+ OPSCC patient (p < 0.0001). Low GDF-15 levels corresponded to longer OS in both HPV- and HPV+ OPSCC. In two independent melanoma patient cohorts treated with nivolumab or pembrolizumab low baseline serum GDF-15 levels were predictive for clinical response to anti-PD1 treatment and superior OS. Bivariate analysis including LDH indicates that GDF-15 independently predicts poor survival in aPD-1 treated melanoma patients. Conclusions: Taken together our in vitro and in vivo data show that elevated GDF-15 levels block T-cell infiltration into tumor tissues. Neutralizing GDF-15 with CTL-002 restores the ability of T cells to extravasate blood vessels and enter tumor tissue both in vitro and in vivo. In melanoma, patients with higher GDF-15 levels have significantly shorter survival and are less likely to respond to anti-PD1 therapy. GDF-15 may thus serve as a new predictive biomarker for anti-PD1 response, but most importantly also represents a novel target for cancer immunotherapy to improve tumor immune cell infiltration and response to anti-PD1 therapy.

Contribution of macrophages to fetomaternal immunological tolerance

The semi-allogeneic fetus develops in a uniquely immune tolerant environment within the uterus. For successful pregnancy, both the innate and adaptive immune systems must favor acceptance of the fetal allograft. Macrophages are the second most abundant immune cells after natural killer (NK) cells in the decidua. In coordination with decidual NK cells and dendritic cells, macrophages aid in implantation, vascular remodeling, placental development, immune tolerance to placental cells, and maintenance of tissue homeostasis at the maternal-fetal interface. Decidual macrophages show the classical activated (M1) and alternatively activated (M2) phenotypes under the influence of the local milieu of growth factors and cytokines, and appropriate temporal regulation of the M1/M2 switch is vital for successful pregnancy. Disturbances in the mechanisms that control the M1/M2 balance and associated functions during pregnancy can trigger a spectrum of pregnancy complications ranging from preeclampsia and fetal growth restriction to preterm delivery. This review addresses various mechanisms of tolerance, focusing on the basic biology of macrophages, their plasticity and polarization, and their protective roles at the immune-privileged maternal-fetal interface, including direct and indirect roles in promoting fetomaternal immune tolerance.

A possible role for HLA-G in development of uteroplacental acute atherosis in preeclampsia

HLA-G, a non-classical HLA molecule expressed by extravillous trophoblasts, plays a role in the maternal immune tolerance towards fetal cells. HLA-G expression is regulated by genetic polymorphisms in the 3′ untranslated region (3′UTR). Low levels of HLA-G in the maternal circulation and placental tissue are linked to preeclampsia.Our objective was to investigate whether variants of the 3′UTR of the HLA-G gene in mother and fetus are associated with acute atherosis, a pregnancy specific arterial lesion of the decidua basalis that is prevalent in preeclampsia.Paired maternal and fetal DNA samples from 83 normotensive and 83 preeclamptic pregnancies were analyzed. We sequenced the part of the HLA-G 3′UTR containing a 14-bp insertion/deletion region and seven single nucleotide polymorphisms (SNPs). Associations with acute atherosis were tested by logistic regression.The frequency of heterozygosity for the 14-bp polymorphism (Ins/Del) and the +3142 SNP (C/G) variant in the fetus are associated with acute atherosis in preeclampsia (66.7 % vs. 39.6 %, p = 0.039, and 69.0 % vs. 43.4 %, p = 0.024). Furthermore, the fetal UTR-3 haplotype, which encompasses the 14-bp deletion and the +3142G variant, is associated with acute atherosis in preeclampsia (15 % vs. 3.8 %, p = 0.016).In conclusion, HLA-G polymorphisms in the fetus are associated with acute atherosis. We hypothesize that these polymorphisms lead to altered HLA-G expression in the decidua basalis, affecting local feto-maternal immune tolerance and development of acute atherosis.

Controlled induction of immune tolerance by mesenchymal stem cells transferred by maternal microchimerism

Feto-maternal immune tolerance is established during pregnancy; however, its mechanism and maintenance remain underexplored. Here, we investigated whether mesenchymal stem/stromal cells (MSCs) as non-inherited maternal antigens (NIMAs) transferred by maternal microchimerism could induce immune tolerance. We showed that MSCs had a potential equivalent to hematopoietic stem and progenitor cells (HSPCs) to induce immune tolerance and that MSCs were essential to induce tolerance to MSC-specific antigens. Furthermore, we demonstrated that MSCs as NIMAs transferred by maternal microchimerism could induce robust immune tolerance that can be further enhanced using a drug. Our data shed light on induction of immune tolerance and serve as a foundation to develop new therapies using maternally derived cells for autoimmune or genetic diseases.

Recurrent Spontaneous Abortion (RSA) and Maternal KIR Genes: A Comprehensive Meta-Analysis.

Natural killer cells (NKs) are the most important cells in the fetomaternal immune tolerance induced through interaction of maternal killer-cell immunoglobulin-like receptors (KIR) and fetal human leucocyte antigens (HLA). Hence, we intend to perform a meta-analysis on the role of maternal KIR genes diversity in recurrent spontaneous abortion (RSA). The present paper is a meta-analysis of previous genetic association studies and our previous original study. The results showed that KIR3DL1 was a significantly protecting factor for RSA (p=0.044; OR=0.833 [0.698-0.995]; fixed effect model). KIR2DS2 (p=0.034; OR=1.195 [1.013-1.408]; fixed effect model) and KIR2DS3 (p=0.013; OR=1.246 [1.047-1.483]; fixed effect model) were significantly risk factors for RSA. For KIR2DS1 there was a high heterogeneity and publication bias. Briefly, the inhibitory gene KIR3DL1 was a protecting factor, and the activating genes KIR2DS2 and KIR2DS3 were risk factors for RSA. However, the effect sizes were not suitable. We suggest further studies on different causes of pregnancy loss, to find the role of KIR2DS1.

THE ROLE OF GLYCODELIN IN THE REGULATION OF THE IMMUNE SYSTEM IN THE CONTEXT OF DEVELOPING PREGNANCY

The review presents data on the role of glycodelin A (GdA, PP14, α2-PEG, EP15, PEP, AUP, PAEP) in regulating the functions of the immune system in the context of the formation of feto-maternal immune tolerance during pregnancy. Glycodelin was first isolated and identified in 1976 by D.D. Petrunin. and Tatarinov Yu.S. with colleagues as a new placenta antigen, which was named chorionic α2-microglobulin. Since then, a huge amount of scientific data has been obtained on the structure, properties, and biological effects of this glycoprotein. This protein has four differentially glycosylated isoforms, namely GdA, GdF, GdC, and GdS, which are secreted in different parts of the reproductive system. The most studied isoform, glycodelin A (GdA), is secreted by the decidual glandular epithelium and accumulates in the amniotic fluid and maternal serum during pregnancy. GdA level is a sign of endometrial fertile function. GdA has diverse biological effects, in particular, it modulates endocrine function and differentiation of trophoblast cells. The role of GdA in the regulation of the immune system is to inhibit the proliferation of T and B lymphocytes, suppress the cytotoxicity of NK cells, induce apoptosis of activated CD4+ cells, monocytes and NK cells, inhibit the activity of cytotoxic T lymphocytes and suppress the functional activity of macrophages and dendritic cells. In addition, GdA increases the level of regulatory T cells, regulates the Th1/Th2 balance towards Th2, and induces a tolerant phenotype of dendritic cells. The immunomodulating activity of GdA depends on the degree of its glycosylation, which, in turn, is associated with the preparation obtaining method. Therefore, the review analyzed the features of the immunomodulating effects of the native and recombinant types of glycodelin on the immune system cells. However, the cumulative effects of GdA on the cells of the immune system make it possible to consider it as one of the main factors shaping the feto-maternal immune tolerance during pregnancy. It is also important to note that clinical studies have revealed a correlation between low levels of circulating GdA and repetitive spontaneous abortions that confirms the importance of this protein in fetoprotection. In general, it is obvious that GdA has the potential as a medicinal preparation for autoimmune deseases treatment, post-transplant complications and in vitro “reprogramming” of autoreactive T-cell clones for further cellular immunotherapy.

Extracellular vesicle mediated embryo-endometrial cross talk during implantation and in pregnancy.

Extracellular vesicles are lipoproteinaceous membrane-enclosed nanometer-sized structures produced by cells and are thought to mediate cellular communications. Loaded with a specific set of miRNA and protein depending on their tissue of origin, these extracellular vesicles modulate diverse set of biological processes in their target tissues. In recent years, data has gathered on the roles of extracellular vesicles in embryo implantation and pregnancy. Embryo, oviduct, endometrial epithelium and stroma/decidua derived vesicles interact with trophoblast cells and promote their growth and differentiation to aid in embryo implantation. The placental vesicles are detected in maternal circulation that aids in feto-maternal immune tolerance, their levels vary in women with pregnancy-related complications like preeclampsia. Beyond the host, the microbes in the genital tract are also reported to produce extracellular vesicles which are thought to be responsible for inflammation and preterm births. This review focuses on the extracellular vesicular trafficking involved in success of pregnancy.

Analysis of PD-L1 expression in trophoblastic tissues and tumors

The immune checkpoint proteins, programmed death receptor 1 (PD-1) and programmed death ligand 1 (PD-L1), are crucial for maintaining fetomaternal immune tolerance and immune escape in cancers. In this study, we performed a comprehensive immunohistochemical study of PD-L1 expression in a large cohort of trophoblastic tissues and tumors. We found that normal villi and hydatidiform moles showed a heterogeneous PD-L1 staining among trophoblast (strong in syncytiotrophoblast, moderate in intermediate trophoblast, and weak/negative in cytotrophoblast). Eleven exaggerated placental sites (100%) showed variable PD-L1 staining, whereas 7 (36.8%) of 19 placental site nodules/plaques were weakly positive for PD-L1 (P < .001). All gestational choriocarcinomas (CCs; n = 63), epithelioid trophoblastic tumors (n = 12), and placental site trophoblastic tumors (n = 41) were PD-L1 positive, with most showing strong staining. However, PD-L1 expression was lower in epithelioid trophoblastic tumors compared with placental site trophoblastic tumors and CCs (P = .004). Three presumably germ cell-derived pure CCs, the CC elements in 13 mixed germ cell tumors, and 4 gastric/rectal CCs were also positive for PD-L1, with widespread staining. The background nontrophoblastic tissues, such as endometrial glands, squamous cells, and adenocarcinomas, were PD-L1 negative. Western blot analysis showed that PD-L1 was expressed in all 3 trophoblastic cell lines. We conclude that PD-L1 is a sensitive but nonspecific marker for trophoblast and related tumors. The frequent strong PD-L1 expression suggests that immune checkpoint blockade could be a promising approach in treating trophoblastic tumors that merits further investigation.

Innate immune cells in reproduction.

Fetomaternal immune tolerance is required to prevent fetal rejection during pregnancy; simultaneously, the maternal immune system must also protect the fetus from harmful endogenous and exogenous antigens, including those associated with viral and bacterial infections. Therefore, a delicate immune balance is critical for the maintenance of a successful pregnancy, while disruption of this balance can induce complications such as implantation failure, miscarriage, preterm birth/labor, preeclampsia and fetal growth restriction. While the adaptive immune system is critical for the development of tolerance, this review summarizes evidence that modulation of the innate immunity is also essential for achieving this delicate balance between tolerance and protection. Canonical cells of the innate immune system, including dendritic cells, macrophages, natural killer cells and invariant natural killer T cells, contribute to the modulation of the immune balance at the fetomaternal interface. The newly identified myeloid-derived suppressor cells and innate lymphoid cells also appear important for successful reproduction. Moreover, it is possible that sterile inflammation facilitates complications of pregnancy via the innate immune system. In this review, the characteristic features and functions of innate immune cells in fetomaternal immunity and their contributions to pregnancy complications related to sterile inflammation are discussed. These insights on innate immune system function in reproduction may provide new perspectives for understanding the mechanisms of fetomaternal tolerance and the etiology of pregnancy complications.

Are aggressive epithelial cancers 'a disease' of Eutherian mammals?

Placental immune editing switches (PIES) have not evolved to prevent or to cause cancer but to make feto-maternal immune tolerance possible, which is at the very core of our placental mammalian (‘Eutherian’) nature. Aggressive epithelial cancers might be an unfortunate ‘side effect’ of this highly sophisticated biological nature. Microenvironmental properties in the placenta and decidua are thought to be a key to feto-maternal immune tolerance. Recently, in 2016–2018, we published the first human genomic and epigenomic evidence of similar gene expression profiles in immune regulatory genes in cancer (primary lobular infiltrating breast cancer and ipsilateral axillary metastatic lymph nodes) and both placenta and decidua of the same young patient with breast carcinoma during pregnancy. These findings led us to speculate that ectopic expression, or repression, of ‘PIES’ might be used by cancer cells during carcinogenesis or cancer progression to elude immune vigilance in spite of tumour-associated antigens or evolving neo antigenic landscapes. Cancers are well known to frequently express embryonic antigens, such as carcinoembryonic antigen, used as cancer markers and detectable in the blood circulation, or to express ectopic hormones. Why should cancer cells invent de novo complex new immune suppression mechanisms, if they could simply use innate ones developed during the long-term evolution of placental mammals in order to hide fetal paternal antigens from the mother’s own immune system?Monotremata (Prototheria-like Echidnas or Platypus Ornithoryncus) are nonplacental egg-laying mammals and, in spite of rudimentary breast epithelial ducts and lobules, they are seldom reported to suffer from aggressive breast cancers.

An investigation of the relationship between recurrent spontaneous abortion and memory T follicular helper cells.

Immune tolerance with respect to a semi-allogeneic fetus plays a key role in the establishment of a pregnancy. Memory T follicular helper (Tfh) cells have a central role in the regulation of the adaptive immune response. Much of our knowledge of memory Tfh cells' function comes from immune-related diseases. However, the true physiological characteristics of memory Tfh cells and their mode of action in pregnancy remain unclear. Deciduas and blood were obtained from 25 recurrent spontaneous abortion (RSA) patients undergoing surgical abortion and 19 normal women in early pregnancy undergoing elective termination. RSA patients were grouped into antibody-positive patients and antibody-negative patients, respectively. The memory Tfh cells with the CD4+ CXCR5+ PD1+ CCR7- and CD4+ CXCR5+ PD-1+ ICOS+ phenotypes were assessed by flow cytometry. The B cells were evaluated by flow cytometry. A correlation analysis of the subsets of memory Tfh cells and B cells in antibody-positive RSA patients was made by the Pearson test. Memory Tfh cells with the CD4+ CXCR5+ PD1+ CCR7- and CD4+ CXCR5+ PD-1+ ICOS+ phenotypes showed a significant increase in RSA patients compared to women with a normal pregnancy who had chosen termination. When RSA patients were grouped according positive or negative antibodies, it was surprising to find that decidual CD4+ CXCR5+ PD-1+ ICOS+ memory Tfh cells significantly increased in RSA patients with positive antibody compared to RSA patients with negative antibody. However, the percentages of CD4+ CXCR5+ PD1+ CCR7- memory Tfh cells did not change in the deciduas of the two groups. Circulating and decidual B cells significantly increased in antibody-positive RSA patients compared with antibody-negative RSA patients. Correlation analysis indicated a strong association between the decidual CD4+ CXCR5+ PD-1+ ICOS+ memory Tfh cells and B cells in antibody-positive RSA patients. These new findings provide unique insights into memory Tfh cells in mediating feto-maternal immune tolerance.

Fyn Plays a Pivotal Role in Fetomaternal Tolerance Through Regulation of Th17 Cells.

Spontaneous abortion is a poorly understood phenomenon, although fetomaternal intolerance is known to play an important role in its pathogenesis. The tyrosine-specific phosphotransferase Fyn has been reported as a significant regulator in immune response. However, its role in fetomaternal immune tolerance and contribution to spontaneous abortion remains unclear. Fyn expression was evaluated at the fetomaternal interface of normal pregnant and abortion-prone mice, as well as in decidual tissue obtained from normal human pregnancies and idiopathic miscarriages. A Fyn inhibitor was administrated into the LPS-induced abortion mice to investigate the variation of embryo resorption and local immunity. Fyn expression fluctuated with the progress of normal pregnancy and was elevated in abortion-prone mice and patients with recurrent spontaneous abortion. The Fyn inhibitor reversed LPS-induced embryo absorption and aberrant inflammatory status including redundant expression of IRF4 and increased proportion of Th17 cells. Fyn is confirmed as a negative regulator in fetomaternal immune tolerance, through promoting Th17 cell expansion and proinflammatory factors expression.

Maternal and fetal HLA-G 14 bp gene polymorphism in pregnancy-induced hypertension, preeclampsia, intrauterine growth restricted and normal pregnancies

Objective: Trophoblast expression of Human Leukocyte Antigene-G (HLA-G) is essential for feto-maternal immune tolerance and successful placentation. There is contradicting evidence on the relationship between HLA-G polymorphisms and preeclampsia (PE), intrauterine growth restriction (IUGR) and pregnancy-induced hypertension (PIH). Here, we investigate the association between both maternal and fetal HLA-G 14 bp insertion/deletion polymorphism and obstetrical complications. Methods: Clinical and genetic data of 282 women/fetuses (31 severe PE, 8 mild PE, 46 IUGR, 42 PIH and 155 controls) were analyzed both individually and jointly under a codominant, a dominant and a recessive model. Results: HLA-G 14 bp polymorphism was not associated with obstetrical complications, considering the mother and fetus genotypes both jointly and individually. Conclusions: With this study we filled several gaps occurring in previous studies: we analyzed a very well-defined population of PE, PIH and IUGR pregnancies, considering both fetal and maternal HLA-G 14 bp polymorphism, individually and jointly. Our findings showed that fetal and maternal HLA-G 14 bp genotypes are not associated with increased risk for the development of obstetrical complications, suggesting that this polymorphism has no immuno-modulatory role in the development of PE, PIH or IUGR.

Immune system modifications and feto-maternal immune tolerance

Objective This review aimed at understanding pregnancy-induced changes in the maternal immune response and mechanisms for the establishment of feto-maternal tolerance. Data sources Articles cited in this review were obtained from PubMed in English from 2000 to 2014, and the search string included keywords such as feto-maternal tolerance, dendritic cells, macrophage, T regulatory cells, natural killer cells, cytokines and hormone. Study selection Articles regarding altered maternal immune response, including the proliferation and differentiation of the altered cells, and the production of cytokines and regulation of hormones in the feto-maternal interface were retrieved, reviewed and analyzed. Results The changes in immune cells and cytokines in the local uterine microenvironment and peripheral blood are correlated with the establishment of feto-maternal tolerance. The endocrine system regulates the maternal immune system, promoting modifications during pregnancy. In these regulatory networks, every factor is indispensible for others. Conclusions The integration and balance of these immune factors during pregnancy give rise to an environment that enables the fetus to escape rejection by the maternal immune system. This progress is complicated, and needs more comprehensive exploration and explanation.

A study on the role of HLA-G 14bp and ACE IN/DEL polymorphisms in pre-eclamptic South Indian women.

Pre-eclampsia (PE) is a pregnancy specific syndrome characterized by hypertension and proteinuria. Defective placentation during early stages of pregnancy in combination with maternal and environmental factors could lead to systemic inflammation, endothelial dysfunction and the manifestation of the clinical symptoms. HLA-G is considered essential for feto-maternal immune tolerance and successful placentation in pregnancy. ACE promotes decidualization, trophoblast proliferation and plays an important role in blood pressure homeostasis. The HLA-G 14bp and ACE IN/DEL polymorphisms have been reported to be associated with the development of pre-eclampsia (PE). The present study aimed at investigating the role of HLA-G and ACE gene polymorphisms in the aetiopathogenesis of PE. A total of 412 (206 PE patients and 206 normal pregnant women) blood samples were collected from Govt. maternity hospital, Hyderabad, India. Genotyping was carried out for both the genes using PCR followed by PAGE for HLA-G and AGE for ACE gene polymorphisms. DD(ACE) genotype was observed to be elevated (52.9% vs. 31.1%) in the patient group and ID(ACE) (29.6% vs. 54.8%) in the control group (p<0.05). However, HLA-G polymorphism did not differ between patients and controls (p>0.05). Further, combined genotype analysis revealed ID(HLA-G) DD(ACE) to be predisposing genotypes and ID(HLA-G) ID(ACE) to be protective toward preeclampsia in south Indian Women. The ACE genotype (DD(ACE)) is associated with high levels of angiotensin and seems to predispose the individual to PE. However, women carrying the intermediate levels of ACE and HLA-G associated combined genotype (ID(HLA-G) ID(HLA-G)) appear to be protective against developing PE.

Human decidual macrophages suppress IFN-γ production by T cells through costimulatory B7-H1:PD-1 signaling in early pregnancy

In human pregnancy, CD14+ decidual macrophages (DMs) are the dominant professional antigen-presenting cells in the decidua, comprising 20–30% of the local leukocyte population. Although the relevance of DMs to feto-maternal immune tolerance has been described, the molecular mechanisms underlying these functions have not been fully elucidated. B7-H1, a costimulatory ligand in the B7 family, negatively modulates T cell activity by binding to its corresponding receptor, PD-1. The present study aimed to investigate the functional significance of costimulatory interactions between DMs and T cells, with a particular focus on B7-H1:PD-1 signaling. An analysis of the expression profile of B7 ligands on human DMs revealed that B7-H1 was present on DMs isolated from early but not term pregnancies. B7-H1 was not expressed on the peripheral monocytes (PMs) of pregnant women. In response to IFN-γ, B7-H1 expression was induced on PMs and was enhanced on DMs, suggesting that this cytokine might be a key factor in the control of B7-H1 expression in the decidua. The majority of decidual T cells were noted to exhibit robust expression of PD-1, whereas the expression was limited to a small subpopulation of circulating T cells. Functional assays demonstrated that DMs are able to suppress T cell IFN-γ production via B7-H1:PD-1 interactions. This suppressive property was not observed for PMs, which lack B7-H1. B7-H1 on DMs may function as a key regulator of local IFN-γ production and thereby contribute to the development of appropriate maternal immune responses to the fetus in early pregnancy.

Sexual intercourse with pyospermia decreases uterine CD16-/CD56 bright natural killer cells in women with infertility

PROBLEM: In the uterine endometrium and the first trimester decidua, there are a number of immune cells derived from the bonemarrow that are capable of responding to alloimmune stimulations from the embryo. Themain population of endometrial NK cell is cytokine producing CD16-/CD56bright NK cells, whereas the most abundant population in peripheral blood NK cells is cytotoxic CD16+/CD56dim NK cells. We previously reported that the increase in cytotoxic NK cells in peripheral blood and the endometrium have a beneficial effect on the therapeutic results of in vitro fertilization andembryo transfer (IVF-ET). Wehave also reported that seminal plasmaplays an important role in the recruitment of CD56bright NK cells into the endometrium. The present study was aimed to investigate the influence of sexual intercourse onNK cell subsets in the mid-secretory endometrium using flow cytometry. METHODS: This study was designed as a prospective study. All study subjects had signed informed consents prior to entry to this study, in accordance with local IRB protocol. All subjects who were planning to have invitro fertilization and embryo transfer (IVF-ET) had sexual intercourse before the endometrial sampling without any contraceptive devices. The mid-secretary endometrium was obtained from 234 women, and then submitted for flow cytometric analysis. Endomerial NK cell subpopulation was analyzed for the expression of CD16 and CD56 using 3-color flow cytometry. Semen analysis was performed at the time of oocytes pick up and was classified according to the World Health Organization (WHO) 2010 guideline. Of 234 semen samples, 10 were diagnosed as pyospermia (pyospermia group), and 224 as not-pyospermia (non-pyospermia group). RESULTS: There were no differences between 2 groups in the total sperm concentration and the motile sperm concentration, or in the percentage of CD56+ NK cells. The percentage of CD16-/CD56+ cells, however, was lower in pyospermia group (25.9±21.7%) compared with that in non-pyospermia group (35.4±18.2%). The percentage of CD16-/CD56bright cells was significantly lower in pyospermia group (28.0±27.8%) compared with that in not-pyospermia group (42.9±22.1%, p< 0.01). CONCLUSIONS: Our study firstly demonstrated that pyospermia has a harmful influence on endometrial NK cell subsets. The immunologically advantageous condition for successful pregnancies after sexual intercourse may give support to the hypothesis that seminal fluid may act as a regulator of endometrial immune cells and an inducer of feto-maternal immune tolerance. Further research should be undertaken to reveal the biological actions of seminal munology 94 (2012) 5–130

CD1d-independent NKT cells and feto-maternal immune tolerance

CD1d-independent NKT cells and feto-maternal immune tolerance