Emerging role of C5aR2: novel insights into the regulation of uterine immune cells during pregnancy.

Pregnancy is a fascinating immunological phenomenon because it allows allogeneic fetal and placental tissues to survive inside the mother. As a component of innate immunity with high inflammatory potential, the complement system must be tightly regulated during pregnancy. Dysregulation of the complement system plays a role in pregnancy complications including pre-eclampsia and intrauterine growth restriction. Complement components are also used as biomarkers for pregnancy complications. However, the mechanisms of detrimental role of complement in pregnancy is poorly understood. C5a is the most potent anaphylatoxin and generates multiple immune reactions via two transmembrane receptors, C5aR1 and C5aR2. C5aR1 is pro-inflammatory, but the role of C5aR2 remains largely elusive. Interestingly, murine NK cells have been shown to express C5aR2 without the usual co-expression of C5aR1. Furthermore, C5aR2 appears to regulate IFN-γ production by NK cells in vitro. As IFN-γ produced by uterine NK cells is one of the major factors for the successful development of a vital pregnancy, we investigated the role anaphylatoxin C5a and its receptors in the establishment of pregnancy and the regulation of uterine NK cells by examinations of murine C5ar2-/- pregnancies and human placental samples. C5ar2-/- mice have significantly reduced numbers of implantation sites and a maternal C5aR2 deficiency results in increased IL-12, IL-18 and IFN-γ mRNA expression as well as reduced uNK cell infiltration at the maternal-fetal interface. Human decidual leukocytes have similar C5a receptor expression patterns showing clinical relevance. In conclusion, this study identifies C5aR2 as a key contributor to dNK infiltration and pregnancy success.

Uterine macrophages and NK cells exhibit population and gene-level changes after implantation but maintain pro-invasive properties.

Introduction: Prior to pregnancy, hormonal changes lead to cellular adaptations in the endometrium allowing for embryo implantation. Critical for successful pregnancy establishment, innate immune cells constitute a significant proportion of uterine cells prior to arrival of the embryo and throughout the first trimester in humans and animal models. Abnormal uterine immune cell function during implantation is believed to play a role in multiple adverse pregnancy outcomes. Current work in humans has focused on uterine immune cells present after pregnancy establishment, and limited in vitro models exist to explore unique functions of these cells. Methods: With single-cell RNA-sequencing (scRNAseq), we comprehensively compared the human uterine immune landscape of the endometrium during the window of implantation and the decidua during the first trimester of pregnancy. Results: We uncovered global and cell-type-specific gene signatures for each timepoint. Immune cells in the endometrium prior to implantation expressed genes associated with immune metabolism, division, and activation. In contrast, we observed widespread interferon signaling during the first trimester of pregnancy. We also provide evidence of specific inflammatory pathways enriched in pre- and post-implantation macrophages and natural killer (NK) cells in the uterine lining. Using our novel implantation-on-a-chip (IOC) to model human implantation ex vivo, we demonstrate for the first time that uterine macrophages strongly promote invasion of extravillous trophoblasts (EVTs), a process essential for pregnancy establishment. Pre- and post-implantation uterine macrophages promoted EVT invasion to a similar degree as pre- and post-implantation NK cells on the IOC. Conclusions: This work provides a foundation for further investigation of the individual roles of uterine immune cell subtypes present prior to embryo implantation and during early pregnancy, which will be critical for our understanding of pregnancy complications associated with abnormal trophoblast invasion and placentation.

Terminological discrepancies and novelties in the histological description of the female genital system: proposed amendments for clinical-translational anatomy.

Histological terminology of the female genital organs is currently a part of the internationally accepted nomenclature Terminologia Histologica (TH), the latest edition of which dates back to 2008. Many new discoveries have been documented within 16 years since then, and many discrepancies have been found. This paper aims to revise the terminology from clinical and educational perspectives comprehensively. The authors thoroughly searched the current edition of "Terminologia Histologica: International Terms for Human Cytology and Histology," focusing on missing and controversial terms in the chapter Female genital system. The authors identified six controversial and ambiguous terms and four missing important histological terms. The authors also discussed the addition of less used eponymic terms in the histological description of female genital organs like Hamperl cells, Popescu cells, Kroemer lacunae, Balbiani bodies, Call-Exner bodies, membrane of Slavianski, nabothian cysts, or anogenital sweat glands of van der Putte. We expect the second and revised edition of the TH to be published soon and hope that the Federative International Program on Anatomical Terminology will approve and incorporate all these propositions and suggestions. We also strongly recommend using the official internationally accepted Latin and English histological nomenclature-the TH, either in oral or written form, both in theoretical and clinical medicine.

Immunohistochemical Evaluation of NKP46 Receptor Expression and the Number of NK Cells in the Endometrium of Patients with Endometriosis.

Background: Endometriosis is a medical condition that can cause infertility in women. Women with endometriosis experience a decrease in NK cell cytotoxic activity against endometrial cells, ultimately contributing to the spread of these cells. Objective: To assess the frequency of NK cells and the expression of the NKP46 receptor in endometrial tissue from patients with endometriosis using immunohistochemistry. Methods: 30 endometrial tissue specimens were collected from three groups of cases with mild (n=11), moderate (n=10), and severe endometriosis (n=9), respectively. Additionally, 20 normal endometrial tissue specimens were collected as the control group. Immunohistochemical staining was carried out using specific human monoclonal antibodies against CD56 and NKP46 molecules. Results: Cases with severe endometriosis had a significantly higher number of CD56+ uterine NK cells (26.19±2.50) compared to fertile women (15.02±0.622) and women with mild to moderate endometriosis (p<0.001). However, there was no significant difference between the mild to moderate patients compared with the healthy women (p>0.05). Endometrial NKp46 expression was lower in women with severe endometriosis (0.447±0.0829) compared to fertile women (0.987±0.115, p=0.03). The NKp46+/CD56+ cell ratio was also lower in women with severe endometriosis (0.019±0.003) compared to fertile women (0.072±0.011, p=0.01). Conclusion: Women with severe endometriosis demonstrated an increased rate of infiltrated uterine NK cells and a significant decrease in NKP46 expression compared to fertile women. Therefore, NK cells and the NKp46 receptor may be involved in the development of endometriosis.

NK and T Cell Subtypes in the Endometrium of Patients with Recurrent Pregnancy Loss and Recurrent Implantation Failure: Implications for Pregnancy Success.

BACKGROUND: RPL and RIF are challenges in reproductive medicine. The immune system plays a pivotal role in endometrial receptivity, successful implantation, and pregnancy complications. Immunological changes have been associated with RPL and RIF. Understanding immune dysregulation especially in NK and T cell subtypes may lead to better diagnostic concepts and treatments. From July 2019 to August 2020 patients with RPL and RIF underwent a standardized diagnostic procedure including endometrial biopsies. Immune cell analysis was performed using flow cytometry. Patients were contacted in March 2023 and interviewed concerning their pregnancy outcomes following diagnostics. RESULTS: Out of 68 patients undergoing endometrial biopsies, 49 patients were finally included. Live birth rates were high with 72% in RPL and 86% in RIF. Immune cell analysis revealed that patients with RPL had more cytotoxic CD56dimCD16high cells, while RIF patients had more CD56+ uNK cells. RPL patients with pregnancy complications showed increased NKT cell percentages. CONCLUSION: Our findings suggest specific immune changes in RPL and RIF patients, offering potential therapeutic targets. Tailored immunotherapy based on endometrial immunophenotyping might be an option, but further research is needed.

The Neglected Uterine NK Cells/Hamperl Cells/Endometrial Stromal Granular Cell, or K Cells: A Narrative Review from History through Histology and to Medical Education.

Reproductive immunology is at the forefront of research interests, aiming to better understand the mechanisms of immune regulation during gestation. The relationship between the immune system and the implanting embryo is profound because the embryo is semi-allogenic but not targeted by the maternal immune system, as expected in graft-versus-host reactions. The most prominent cell population at the maternal-fetal interface is the population of uterine natural killer (uNK) cells. Uterine NK cells are two-faced immunologically active cells, bearing comparison with Janus, the ancient Roman god of beginnings and endings. Their first face can be seen as natural killer cells, namely lymphocytes, which are critical for host defense against viruses and tumors. Even though uNK cells contain cytolytic molecules, their cytotoxic effect is not applied to classical target cells in vivo, playing a permissive rather than a defensive role. Their second face is crucial in maintaining physiological gestation-uNK cells show critical immunomodulatory functions with the potential to control embryo implantation and trophoblast invasion, regulate placental vascular remodeling, and promote embryonic/fetal growth. Therefore, we believe that their current designation "natural killer cells" (the first "cytotoxic" Janus's face) is misleading and inappropriate, considering their principal function is supporting and maintaining pregnancy. In this narrative review, we will focus on three lesser-known areas of knowledge about uNK cells. First, from the point of view of histology, we will comprehensively map the history of the discovery of these cells, as well as the current histological possibilities of their identification within the endometrium. To be brief, the discovery of uNK cells is generally attributed to Herwig Hamperl, one of the most influential and prominent representatives of German pathology in the 20th century, and his co-worker, Gisela Hellweg. Secondly, we will discuss the interesting aspect of terminology, since uNK cells are probably one of the human cells with the highest number of synonymous names, leading to significant discrepancies in their descriptions in scientific literature. From the first description of this cell type, they were referred to as endometrial granulocytes, granular endometrial stromal cells, or large granular lymphocytes until the end of the 1980s and the beginning of the 1990s of the last century, when the first publications appeared where the name "uterine NK cells" was used. The third area of present review is medical teaching of histology and clinical embryology. We can confirm that uNK cells are, in most textbooks, overlooked and almost forgotten cells despite their enormous importance. In the present narrative review, we summarize the lesser-known historical and terminological facts about uNK cells. We can state that within the textbooks of histology and embryology, this important cell population is still "overlooked and neglected" and is not given the same importance as in fields of clinical research and clinical practice.

CD200S-positive granulated lymphoid cells in endometrium appear to be CD56-positive uterine NK cells.

The eutopic secretory phase endometrium in endometriosis overproduces and releases a soluble immunosuppressive CD200 molecule (CD200L) and is populated by stromal cells that contain a truncated CD200 (CD200S) that promotes a proinflammatory environment. The CD200S+ cell population persists when pregnancy occurs and are abundant in the early pregnancy decidua of women with missed abortion. In the present study, CD200S+, CD56+, and CD68+ cells were enumerated in formalin-fixed paraffin-embedded tissue sections from women with endometriosis and non-endometriosis controls. CD200S+ cells were more numerous than CD68+ macrophages and were similar in number and location to CD56bright endometrial NK cells. In some endometria, there was an additional population of CD200S- CD56+ NK cells. In ectopic endometrial peritoneal deposits and in ectopic myometrial deposits (adenomyosis), CD200S+ cells were less frequent, consistent with the known paucity of CD56+ NK cells in sites of ectopic deposits. CD200S+ cell frequency was greater in stroma surrounding the smaller ectopic cystic deposits. Dual immunofluorescent antibody staining confirmed CD200S+ cells were CD56+ NK cells. CD200S+ NK cell frequency may be greater in endometriosis patients' endometrium and may affect embryo survival in early pregnancy. In our opinion, regulation of alternative splicing that results in CD200S rather than CD200L may provide new diagnostic and therapeutic options for women with endometriosis.

Single-Cell RNA-Sequencing Reveals Interactions between Endometrial Stromal Cells, Epithelial Cells, and Lymphocytes during Mouse Embryo Implantation.

The decidualization of endometrial stromal cells (ESCs) is an essential process facilitating embryo implantation. However, the roles of non-decidualized and decidualized ESCs in regulating the microenvironment of a receptive endometrium remain unclear. We investigated single-cell transcriptomic changes in the uterus of a CD-1 mouse model at the post-implantation stage. The implantation and inter-implantation sites of the uteruses of pregnant mice at 4.5 and 5.5 days post-coitum were dissected for single-cell RNA sequencing. We identified eight cell types: epithelial cells, stromal cells, endothelial cells, mesothelial cells, lymphocytes, myocytes, myeloids, and pericytes. The ESC transcriptome suggests that the four ESC subtypes are involved in the extracellular remodeling during implantation. The trajectory plot of ESC subtypes indicates embryo implantation that involves a differentiation pathway from undifferentiated ESCs (ESC 1) to decidualized ESCs (DEC ESCs), with distinct signaling pathways between the ESC subtypes. Furthermore, the ligand-receptor analysis suggests that ESCs communicate with epithelial cells and immune cells through nectin and ICAM signaling. Collectively, both decidualized and non-decidualized ESCs may regulate the endometrial microenvironment for optimal endometrial receptivity and immune tolerance. This study provides insights on the molecular and cellular characteristics of mouse ESCs in modulating the epithelial and lymphocyte functions during early embryo implantation.

Uterine natural killer cells and recurrent spontaneous abortion.

Recurrent spontaneous abortion (RSA), termed as two or more consecutive pregnancy loss is a great problem for some women of childbearing age. A large number of evidence confirm that there may be an immune background of RSA. As a member of the innate immune system, uterine natural killer (uNK) cells account for about 70% of total lymphocytes during pregnancy and play a critical role in the establishment and maintenance of pregnancy. This review mainly introduces the phenotype, origin, receptor, and function of uNK cells to illuminate its relationship with RSA.

Conventional microscopy versus digital image analysis for histopathologic evaluation of immune cells in the endometrium.

In the search for a reliable biomarker able to diagnose immunological causes of infertility, uterine immune cells have been widely investigated. As a result, heterogeneous methods and cutoff values of what constitutes an aberrant number of immune cells have been reported, and a standardized method for quantification is needed. The objective of this study was to compare methods for quantification of immune cells visualized with immunohistochemistry in the endometrium of women in fertility treatment. Evaluation of the density of CD56+, CD16+ and CD163+ cells by conventional microscopy on a semiquantitative scale (low, medium and high) was compared to a continuous count using digital image analysis (DIA) reported as percentage positive cells out of the total number of stromal cells and number of positive cells per mm2, respectively. We previously reported the CD56/CD16 ratio as a possible prognostic marker, and therefore the ratios of CD56/CD16 were compared using two different methods for selecting fields for counting with DIA: one method using principles of systematic random sampling, where glands were excluded, and one method analyzing large parts of the tissue including glands. A significant association between conventional microscopy and DIA was found when the semiquantitative scale was compared to medians of positive cells in CD56, CD16 and CD163, respectively, p < 0.001. A systematic significant difference in the ratios of CD56/CD16 was found when comparing the two methods for field selection, p < 0.001. To determine the possible use of these methods, more knowledge of the correlation to clinical outcome is warranted.

Natural killer cells in recurrent miscarriage: An overview.

Recurrent Miscarriage is an early pregnancy complication which affects about 1-3 % of child-bearing couples. The mechanisms involved in the occurrence of recurrent miscarriages are not clearly understood. In the last decade Natural Killer cells have been studied in peripheral blood and uterus in order to determine if there are specific characteristics of Natural Killer cells associated with miscarriage. Different authors have described an increased number of uterine and peripheral blood Natural Killer cells in women with recurrent miscarriages compared to control women. However, its relationship with miscarriage has not been confirmed. In patients with recurrent miscarriage a lack of inhibition of decidua Natural Killer cells can be observed, which leads to a more activated state characterized by higher levels of proinflammatory cytokines. In peripheral blood, it has been also reported a dysfunctional cytokine production by Natural Killer cells, with an increase of interferon-γ levels and a decrease of Interleukin-4. Significant progress has been made in the last decade in understanding the biology of Natural Killer cells, including the identification of new receptors that also contribute to the activation and regulation of Natural Killer cells. In this review, we summarize the current progress in the study of Natural Killer cells in recurrent miscarriage.

Molecular regulation of vascular smooth muscle cell phenotype switching by trophoblast cells at the maternal-fetal interface.

INTRODUCTION: Establishment of hemochorial placenta is associated with development and remodelling of uterine vasculature at the maternal fetal interface. This results in calibration of high resistance uterine arteries to flaccid low resistance vessels resulting in increased blood flow to the placenta and fetus in humans and rodents. Mechanisms underlying these remodelling events are poorly understood. In this report, we examine regulation of vascular remodelling using vascular smooth muscle cell (VSMC) phenotype switching as a primary parameter. METHODS: Cellular dynamics was assessed by Immunofluorescence, qRT-PCR, western blotting in timed pregnant rat tissue. In vitro co-culture of trophoblast cells with vascular smooth muscle cells was used to understand regulation mechanism. RESULTS: Analysis of cellular dynamics on days 13.5, 16.5 and 19.5 of gestation in the rat metrial gland, the entry point of uterine arteries, revealed that invasion of trophoblast cells preceded disappearance of VSMC α-SMA, a contractile state marker. Co-culture of VSMCs with trophoblast cells in vitro recapitulated trophoblast-induced de-differentiation of VSMCs in vivo. Interestingly, co-culturing with trophoblast cells activated PDGFRß signalling in VSMCs, an effect mediated by secreted PDGF-BB from trophoblast cells. Trophoblast cells failed to elicit its effect on VSMC de-differentiation upon inhibition of PDGFRß signalling using a selective inhibitor. Moreover, co-culturing with trophoblast cells also led to substantial increase in Akt activation and a modest increase in Erk phosphorylation in VSMCs and this effect was abolished by PDGFRß inhibition. DISCUSSION: Our results highlight that trophoblast cells direct VSMC phenotype switching and trophoblast derived PDGF-BB is one of the modulator.

Uterine Natural Killer Cell Heterogeneity: Lessons From Mouse Models.

Natural killer (NK) cells are the most abundant lymphocytes at the maternal-fetal interface. Epidemiological data implicate NK cells in human pregnancy outcomes. Discoveries using mouse NK cells have guided subsequent advances in human NK cell biology. However, it remains challenging to identify mouse and human uterine NK (uNK) cell function(s) because of the dynamic changes in the systemic-endocrinological and local uterine structural microenvironments during pregnancy. This review discusses functional similarities and differences between mouse and human NK cells at the maternal-fetal interface.

Increase in FoxP3, CD56 immune cells and decrease in glands PGRMC1 expression in the endometrium are associated with recurrent miscarriages.

OBJECTIVE: Recurrent miscarriage (RM) is a multifactorial condition that involves frequent uterine anatomical abnormalities, parental karyotype abnormalities, and clotting disorders. We investigate the potential roles of endometrium FoxP3+ Tregs and CD56+ cells (uNK cells) and endometrial expression of PGRMC1 in the development of recurrent miscarriage. STUDY DESIGN: This prospective study included 102 out of 286 cases of SA patients. The cases were divided into groups with RM (+RM) and without RM (-RM). Immunohistochemistry staining was made using primary antibodies to FoxP3, CD56, and PGRMC1 in both groups. Morphometry analyses were carried out in 10 non-overlapping high power fields. Mann-Whitney U test, Fisher two-tail test, correlation analysis and relative risk (RR) were evaluated. A p < 0.05 was considered statistically significant. RESULTS: An increased presence of CD56-positive (p < 0.001) and FoxP3+ Treg (p = 0.0005) cells was found in the endometrium, with a reduction in PGRMC1 expression compared with -RM group (p = 0.004). A positive correlation was shown between the number of CD56-positive cells and FoxP3+ cells (r = 0.55), and an inverse correlation with PGRMC1 (r =  -0.35) in the + RM group. A similar observation was found in the -RM group, with a positive correlation of uNK cell number with the number of pregnancies (p < 0.001; r = 0.34). Endometrial infiltration of CD56-positive (p < 0.0001) and FoxP3+ (p < 0.0001) cells revealed an increased relative risk of RM. This increased risk was also revealed in SA with a loss of PGRMC1 expression (p < 0.0001). CONCLUSION: Our prospective study suggests, for the first time, that increased endometrial infiltration of uNK, FoxP3+ Treg cells and a decreased PGRMC1 expression may play potential roles in the development of RM.

Porphyromonas gingivalis and adverse pregnancy outcome.

Porphyromonas gingivalis is a Gram-negative, anaerobic bacterium considered to be an important pathogen of periodontal disease that is also implicated in adverse pregnancy outcome (APO). Until recently, our understanding of the role of P. gingivalis in APO has been limited and sometimes contradictory. The purpose of this review is to provide an overview of past and current research on P. gingivalis that addresses some of the controversies concerning the role of this organism in the pathogenesis of APO.

Predicting NK cell subsets using gene expression levels in peripheral blood and endometrial biopsy specimens.

PROBLEM: In molecular analysis of tissue biopsy specimens, one crucial aspect is characterization of immune cell populations. This is especially important for evaluation of uterine receptivity by assessing levels of lymphocyte populations including CD56bright CD16- uterine NK cells and CD56dim CD16+ conventional NK cells. Our objective was to investigate whether measuring total RNA transcripts from a tissue specimen would accurately reflect immune cell levels and be a new technique to assess immune cell subsets. METHOD OF STUDY: Peripheral blood mononuclear cells (PBMCs) and endometrial tissues were used. Flow cytometry was utilized for the analysis of lymphocyte subsets in PBMCs, and RT-qPCR was applied to quantify RNA transcripts indicative of lymphocyte and granulocyte populations. RESULTS: In PBMC specimens, there were significant correlations between gene expression levels and cell subsets. NK cells correlated with CD16A, NKp46, and CD56 transcripts, B cells correlated with EBF1, and CD8+ T cells correlated with CD8ß. Finally, endometrial tissues displayed high CD56 expression and very low CD3ε, CD16A, and NKp30, reflecting the characteristic endometrial NK cell subsets. CONCLUSION: Strong correlations between RT-qPCR data and levels of lymphocyte subsets indicate that gene expression analysis will be a useful technique for characterizing levels of CD56+ cells in endometrial tissues.

Uterine NK cells and macrophages in pregnancy.

The presence of immune cells in the placental bed is important for both mother and child. Although various immune cells can be found in the placental bed, such as regulatory T cells and dendritic cells, uterine NK cells and macrophages are the most prominent immune cells in the placental bed in early pregnancy. uNK cell and macrophage numbers in the placental bed decrease in the third trimester. These cells seem to be specifically adapted for their function and environment. uNK cells do not show cytotoxic activity, but are producers of cytokines, growth factors and many other factors. uNK cell function is regulated by inhibitory and activating receptors binding to HLA class I on trophoblast cells. uNK cells are also involved in regulating trophoblast invasion. Macrophages mainly show an M2-like phenotype and also produce cytokines and various other factors. They are important in phagocytosis of various cells and cell debris in the placental bed. Both cell types are also involved in angiogenesis and spiral artery remodeling in the placental bed. In this review we will elaborate on the most important functions of uNK cells and macrophages in the placental bed in humans. We will also discuss animal models, since they may provide clues for function of uNK cells and macrophages in humans.

PIBF positive uterine NK cells in the mouse decidua.

Though uterine NK cells (u NK cells) contain cytotoxic granules, and selectively over- express the genes of perforin and granzymes, during normal pregnancy, they are not cytotoxic. Progesterone is indispensable for the establishment and maintenance of pregnancy both in humans and in mice. Mouse uterine NK cells do not express the classical progesterone receptor, yet progesterone affects the recruitment and function of uterine NK cells, the latter partly via the Progesterone-Induced Blocking Factor (PIBF). We demonstrated PIBF positive granulated cells in the mouse decidua. The aim of this study was to characterize these cells by lectin immunohistochemistry and anti-perforin reactivity. PIBF+ granulated cells were absent from the deciduae of alymphoid mice, but appeared in the decidua of those that had been reconstituted with bone marrow from male BALB/c mice. PIBF+ granulated cells bound the DBA lectin, suggesting their NK cell nature, and also contained perforin, which co-localized with PIBF in the cytoplasmic granules. In anti-progesterone treated mice all of the PIBF+ cells were perforin positive at g. d. 12.5, in contrast to the 54% perforin positivity of PIBF+ cells in untreated mice. CONCLUSION: The PIBF+ granulated cells in the decidua belong to the NK population, and PIPB co-localizes with perforin in the cytoplasmic granules.

The Residual Innate Lymphoid Cells in NFIL3-Deficient Mice Support Suboptimal Maternal Adaptations to Pregnancy.

Uterine NK cells are innate lymphoid cells (ILC) that populate the uterus and expand during pregnancy, regulating placental development and fetal growth in humans and mice. We have recently characterized the composition of uterine ILCs (uILCs), some of which require the transcription factor NFIL3, but the extent to which NFIL3-dependent cells support successful reproduction in mice is unknown. By mating Nfil3 (-/-) females with wild-type males, here we show the effects of NFIL3 deficiency in maternal cells on both the changes in uILCs during pregnancy and the downstream consequences on reproduction. Despite the presence of CD49a(+)Eomes(-) uILC1s and the considerable expansion of residual CD49a(+)Eomes(+) tissue-resident NK cells and uILC3s in pregnant Nfil3 (-/-) mice, we found incomplete remodeling of uterine arteries and decidua, placental defects, and fetal growth restriction in litters of normal size. These results show that maternal NFIL3 mediates non-redundant functions in mouse reproduction.

Cellular Regulation of the Uterine Microenvironment That Enables Embryo Implantation.

Implantation of the fertilized egg into the maternal uterus is a crucial step in pregnancy establishment. Increasing evidence suggests that its success depends on various cell types of the innate immune system and on the fine balance between inflammatory and anti-inflammatory processes. In addition, it has recently been established that regulatory T cells play a superordinate role in dictating the quality of uterine environment required for successful pregnancy. Here, we discuss the cellular regulation of uterine receptivity with emphasis on the function and regulation of cells from the innate and adaptive immune system.