• Users Online: 105
  • Print this page
  • Email this page

 Table of Contents  
Year : 2017  |  Volume : 1  |  Issue : 1  |  Page : 36-44

Immune Regulation at Maternal-fetal Interface in Early Pregnancy

1 Laboratory for Reproductive Immunology, Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Fudan University; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China
2 Laboratory for Reproductive Immunology, Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Fudan University; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases; Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, China

Date of Web Publication17-Jul-2017

Correspondence Address:
Da-Jin Li
Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Zhao Zhou Road 413, Shanghai 200011
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2096-2924.210695

Rights and Permissions

Decidual immune cells (DICs), including T-cells, regulatory T-cells, macrophages/dendritic cells, natural killer cells, and neutrophils, are resident at the maternal–fetal interface, and play vital roles in regulating trophoblast migration, decidual angiogenesis, immune tolerance, placentation, and decidualization during the early pregnancy. Extensive researches have revealed that these maternal DICs cooperated with each other, or with maternal decidual stromal cells, or with fetal-derived trophoblasts, and further formed a special maternal-fetal cross talk at the maternal-fetal interface, which was essential for the construction and maintenance of physiological pregnancy. Once aberrant cross talk and immune regulation arise, many pregnancy complications will inevitably occur, such as spontaneous abortion, intrauterine growth restriction(IUGR), preeclampsia (PE), and preterm birth. Here, we reviewed how critical immune cells are either enriched or excluded from the decidua, how their function is regulated within the decidua, and how they variously contribute to pregnancy success or failure.

Keywords: Cross Talk; Decidual Immune Cells; Decidual Stromal Cells; Pregnancy; Trophoblastic Cells

How to cite this article:
Zhou WJ, Li MQ, Li DJ. Immune Regulation at Maternal-fetal Interface in Early Pregnancy. Reprod Dev Med 2017;1:36-44

How to cite this URL:
Zhou WJ, Li MQ, Li DJ. Immune Regulation at Maternal-fetal Interface in Early Pregnancy. Reprod Dev Med [serial online] 2017 [cited 2022 Jan 26];1:36-44. Available from: https://www.repdevmed.org/text.asp?2017/1/1/36/210695

  Introduction Top

Two distinct physically opposed tissue systems, placenta and decidua, have to coordinate physiologically to ensure successful pregnancy. Decidua in uterus provides blood vessels and a cellular substratum, while placenta functions as the primary nutrient and gas exchange organ of the fetus. These two organs work sustainable till the moment of delivery.[1]

During pregnancy, extravillous trophoblast cells (EVTs) from the fetus invade the decidua and remodel the maternal spiral arteries to provide adequate nutrition to the developing fetus, the process of which is closely associated with an evolutionary immunological scenario of maternal adaption toward the allogeneic fetus.[2],[3],[4],[5] Instead of taking place in isolation, the processes of decidualization and angiogenesis at maternal–fetal interface are subject to a superposed regulation by the maternal immune cells that populate in the decidua.[1] Not only to nourish placental development, the components and functions of these cells are also highly specialized to minimize the chances that the baby and placenta are attacked as a transplanting allogeneic body, as well. Researches have revealed that the multiple mechanisms of the interaction between the fetal trophoblasts and maternal immune systems may be involved in inducing and maintaining immune cell homeostasis during pregnancy.[5]

Moreover, current immunology has revealed intercellular communication not only among lymphoid or myeloid cells, but also involving tissue stromal parenchymal or nonparenchymal cells, which can modify the proportion and extracellular paracrine signaling of lymphoid/myeloid cells by means vulnerable to tissue microenvironment.[6] As indispensable parts at the maternal-fetal interface, decidua and trophoblasts also play important roles in keeping immunologic balance. Previous studies have shown that the differentiation of decidual stromal cells (DSCs), even under conditions of systemic inflammation, can activate an epigenetic program that may transcriptionally silence the expression of the key Th1/CTL-attracting chemokines CXCL9 (MIG), CXCL10 (IP-10), CXCL11 (I-TAC), and CCL5 (RANTES).[7] The inhibition of chemokine production in decidua is associated with methylation of these genes, which suggests that epigenetic regulators control the capacity of the decidua to attract T-cells. Decidua resists infiltration by activated Th1 cells and CTLs, which is independent of cognate antigen expression by the conceptus.[7] Decidua can produce growth factors and cultured endometrial cells can secrete cytokines (interleukin-6 [IL-6], tumor necrosis factor-α [TNF-α]) and chemokines (IL-8, CXCL1), and express the chemokine receptor CXCR4 during normal pregnancy,[8],[9] which is called “nonclassical” communication between the embryo and the decidua.[6]

As we know, to secure and promote pregnancy, a variety of immune cells are recruited to the placental bed, and then synchronized and adaptive responses are required by the conceptus to maintain maternal tolerance. Here, we discuss the immunoregulation of the maternal–fetal interface from several perspectives, including the sources and functions of the immune cells as well as DSCs and trophoblasts.

Both tissue immunostaining and flow cytometry have shown that human decidual leukocytes of the first trimester are primarily natural killer (NK) cells (50%–70%) and macrophages (Mϕs) (approximately 20%).[1],[10],[11] While T-cell proportions are more variable (around 10%–20%), dendritic cells (DCs), B-cells, and NKT cells are rare.[1] In this review, we will explore the role of decidual innate and the adaptive immune cells in facilitating tolerance to the fetus. In particular, we will highlight the recent advances of the interaction between these cells, drawing comparisons between healthy human pregnancy and preeclampsia.

  Decidual Natural Killer Cells Top

The origin and phenotype of dNK

Until now, the origin of dNK cells has not been clearly elucidated. One suggestion is that they may be generated in situ from early progenitors, which then differentiate or proliferate by the stimuli of the environment-enriched steroid hormones and cytokines/chemokines to enlarge the dNK cell population,[12],[13],[14] which has been supported by the evidence that, even before conception, there exists an immature population of NK cells in the uterus.[15] Several studies also proposed that dNK cells may derived from peripheral blood NK (pNK) cells, which could further migrate to the decidua through chemotaxis and further acquire decidual phenotype within the local microenvironment.[12],[16],[17],[18] Previous studies have demonstrated that large amounts of NK-attractant chemokines, including CXCL10/IP-10, CXCL12/SDF-1, CCL2/monocyte chemoattractant protein-1 (MCP-1), CXCL8/IL-8, and CX3CL1/fractalkine, and cytokines (IL-15), were produced by DSCs and invasive EVT, which supported this possibility.[16],[19],[20],[21] The dNK cells would originate from CD56bright pNK cells that are recruited to the decidua following the axis CXCR3-CXCL10 or CXCR4-CXCL12.[16],[19],[20]

Therefore, several origins of dNK populations lead to the heterogeneous chemokine receptor expressions on their surface. On the other hand, despite some similarities, the first-trimester dNK cells and their pNK cell counterparts from the same donor present fairly distinct properties. Most of the dNKs are composed of CD56bright CD16neg cells which are cytokine producers, while the CD56dim CD16pos subset, which constitutes 95% of the total pNK cells, is highly cytotoxic.[22],[23],[24] Most of the CD56dim CD16pos pNK cells express members of the KIR family. In contrast, the majority of CD56bright CD16neg cells lack KIR expression but express high levels of the CD94/NKG2A inhibitory receptor,[25] and similarly to CD56bright CD16neg pNK cells, dNK cells also express high levels of the CD94/NKG2A inhibitory receptor.[26] In addition, the expression of other activating and inhibitory receptors is also different in these two subsets.[27],[28],[29] The dNK cells express a unique spectrum of activating and inhibitory receptors that resembles the early differentiation stages of NK cells, distinguishing them from pNK cells.[22],[23],[24],[27],[28],[29] Unlike resting pNK cells, dNK cells also express the CD69 activation marker and a large fraction express NKp44 activating receptor.[27] However, dNK and pNK cells express similar levels of NKG2D and 2B4 (CD244).[27] Meanwhile, several cytokines, including IL-15, IL-18, or ligation of a specific activating receptor, can induce the cytotoxic function of dNK cell,[22],[30],[31] suggesting that there is a precise regulatory mechanism of the dNK lytic machinery function in the normal pregnancy.

Function of dNK cells

The presence of dNK cells plays critical roles in promoting trophoblast invasion and spiral artery remodeling with their abundant production of various cytokines.[24], 27, [32],[33],[34] Several soluble cytokines, including CXCL10/IP-10, CXCL8/IL-8, CXCL12/SDF-1, and CCL2/MCP-1, promote the recruitment and attraction of fetal trophoblasts.[18],[24],[27],[32],[34] In turn, invasive fetal trophoblasts can assist in the accumulation of dNK cells in decidua through the secretion of chemokines, such as SDF-1 and Mϕ inflammatory protein 1-a (MIP-1a).[20] While the vascular endothelial growth factor (VEGF)-C produced by dNK cells can participate in immune tolerance by inducing MHC-I molecule assembly and TAP-1 expression on trophoblasts.[33] In addition, dNK cells produce various pro-angiogenic growth factors, such as the placental growth factor, VEGF-A, and VEGF-C, which favor angiogenesis.[24],[33],[35] Previous studies have demonstrated that, before the invasion of fetal trophoblasts, the vascular remodeling is initially associated with significant accumulation of dNK cells and decidual macrophages (dMϕs) within the vascular wall.[26],[36] Recent studies have confirmed the contribution of dNK cells to the early phases of vascular remodeling in human pregnancy.[37],[38] In addition, genetic studies suggest that amounts of maternal KIRs and HLA-C genotypes are associated with the defects in trophoblast invasion and the increased risk of recurrent spontaneous abortion (RSA) and intrauterine growth restriction.[19],[39],[40],[41] Moreover, dNK cells may also play a role in decidualization itself since lacking NK cells in mice, the decidua is abnormal and the fetal weights are reduced.[42],[43]

Apart from their role in vascular remodeling and decidualization, dNKs also directly induce immune tolerance. Phosphatidylserine receptor T-cell immunoglobulin mucin-3 (Tim-3), a regulator of both pro- and anti-inflammatory immune responses, has been reported to be upregulated in NK cells during early pregnancy and inhibits the NK cytotoxicity toward trophoblasts in Galectin-9 (Gal-9)-dependent pathway.[44] Consistently, our team has also found that the Gal-9/Tim-3 signal is important for the regulation of dNK cell function, which is beneficial for the maintenance of a normal pregnancy.[45] Moreover, Ophir et al.[46] found that paired Ig-like type 2 receptor alpha binded to an unknown receptor is expressed primarily on CD56bright dNK cells that may lead to elevated interferon-gamma (IFN-γ) secretion and cytotoxicity and activate NK cell functions. Recently, Faust et al.[47] showed that progesterone-induced blocking factor (PIBF) inhibits the cytotoxicity of pNK cells through a block of degranulation without interfering with target conjugation, and Bogdan et al.[48] further discovered that, PIBF, which is present in the cytoplasmic granules, contributes to low decidual NK activity. Generally speaking, these findings suggested that the tolerant microenvironment could be established through cellular cross talks between dNK cells and other cells at the fetal-maternal interface [49],[50] with active interaction between the cytotoxic T-lymphocyte antigen-4 and its ligand or indirect mechanisms producing immunoregulatory molecules, such as transforming growth factor-β (TGF-β), IL-10, or indoleamine 2, 3-dioxygenase (IDO).[51],[52],[53] Apart from cytokines, the dynamic changes in expression levels and patterns of extracellular matrix proteins during the tissue remodeling in early pregnancy [8],[9] might also induce changes in the stromal affinity for dNK cells, as suggested by the tissue distribution of dNK cells.

  Decidual Macrophage Cells Top

The origin and phenotype of decidual macrophage cells

Monocytes play an important role in tissue repair, immune homeostasis, and defense against infection and inflammation [54] to replenish steady-state Mϕs or can be recruited in inflammatory conditions.[55] They mature into Mϕs (or DCs)[55] that are responsible for both innate and adaptive immunity.[56],[57],[58] Although in low numbers, Mϕs are already present in the nonpregnant endometrium.[59] Once fertilization, the expression of various chemokines and the number of uterine Mϕs increase,[60] accounting for about 20%–30% of all decidual leukocytes.[61],[62] Indeed, previous studies have described Mϕ subsets with distinct functions. Broadly, based on the different receptors, cytokines, chemokine expressions, and effector functions, Mϕs can be divided into two groups: M1, classically activated Mϕs, which are microbicidal and inflammatory, and M2, alternatively activated Mϕs, which are immunomodulatory and can induce tolerance and the resolution of inflammation.[63]

According to the gene expression profiling, most uterine Mϕs present a M2 phenotype and function in immune regulation, tissue remodeling, cell proliferation, and metabolism in the early pregnancy uterus.[47],[64] Compared to peripheral blood Mϕs, dMϕs express higher levels of surface markers, including CD206, CD209, tetraspanin CD9, and Mϕ mannose receptor.[50],[65],[66],[67] Apart from those above, dMϕs also express other markers, including trem-2, alpha 2 macroglobulin, and prostaglandin D2 (PGE2) synthase.[64]

In addition, Houser et al.[68] described two distinct subsets of CD14+ dMϕs which were classified by the surface marker CD11c (around 33% were CD11c high and approximately 67% were CD11c low) presenting in first-trimester decidua, which turned out that it did not fit the conventional M1/M2 categorization due to the secretion of pro- and anti-inflammatory cytokines in each of the populations.[68],[69] Considering the complexity of Mϕ biology, the function of dMϕs in tissue remodeling versus inflammation will not be easily attributable to one or other subsets. Tim-3 is also expressed on the surface of Mϕ with higher levels in M2 than M1 Mϕs, suggesting that Tim-3-expressing Mϕs are important in maintaining immune tolerance. In addition, Tim-3-expressing Mϕs have higher phagocytic activity of apoptotic bodies in the pregnant uterus.[70]

The differentiation and function of decidual macrophage cells

Regardless of the origin of dMϕs, their regulation is likely controlled by the surrounding microenvironment. In any tissues, the survival, differentiation, and proliferation of Mϕs at the steady state are under the control of Mϕ growth factors in a tissue-specific manner.[71] Several cytokines and chemokines are vital factors involved in recruiting and regulating dMϕs during pregnancy, including the colony-stimulating factor-1 (CSF-1), which induces proliferation, differentiation, and survival of monocytes/Mϕs,[72] MCP1 (CCL2), MIP-1a (CCL3), and Mϕ migration inhibitory factor from the trophoblast cell.[19],[73] During pregnancy, M-CSF is dramatically increased in the mouse and human uterus,[43],[74],[75] implying a particularly important role in dMϕ polarization. In support of this speculation, M-CSF induces Mϕs with phenotypes (CD163high, CD206high, CD209high, and neuropilin-1high, and ICAM-3low), as well as the cytokine production (IL-10high and TNF low) and gene expression profile that are strikingly similar to those of human dMϕs.[71] It was shown that M-CSF could control the production of CCL2 of mouse uterine Mϕs, suggesting that M-CSF contributes to the continuous recruitment of blood monocytes into the uterus during pregnancy.[75] In contrast to M-CSF, when administered alone, GM-CSF not only induces Mϕs with more pro-inflammatory M1-like characteristics, but also neutralizes the M2-promoting effects of M-CSF.[76] In addition to growth factors, cytokines have a great impact on Mϕ polarization. Like M-CSF, the anti-inflammatory IL-10 is a potent inducer which can induce the characteristics of dMϕs and regulate Mϕs at the fetal–maternal interface.[76]

The dMϕ cells play vital roles in implantation, placental formation, trophoblast invasion, and decidual homeostasis. They can secrete immunoregulatory molecules, such as IL-10,[77] PGE2, TGF-β, and IDO,[78] and involve in immunosuppression.[77] In addition, with the secretion and regulation of proteases, growth factors, chemotactic molecules, cytokines, and various matrix components, dMϕ cells coordinate tissue remodeling and angiogenesis.[78] Furthermore, dMϕ cells also participate in inducing apoptosis of unwanted or damaged cells. This Mϕ-induced apoptosis may be necessary to accommodate the developing fetus in the uterus and to regulate the extent of trophoblast invasion.[79],[80]

Interestingly, immunohistochemical results suggested that Mϕs expressing inhibitory receptors (ILT2 and ILT4) for HLA-G (expressed by EVT) were located in proximity to invading EVT within the placental bed.[79],[80] Indeed, Mϕs with MMP 9-positive and phagocytic capacities have been found to infiltrate spiral arteries during vascular remodeling.[26] On the other hand, dMϕs are also important for the clearance of apoptotic cells in decidua.[72] By phagocytosis of apoptotic cells, Mϕs can prevent the release of pro-inflammatory substances from the apoptotic cells into the decidua.[72] Moreover, recent studies showed that peripheral blood Mϕs, activated by lipopolysaccharides, could inhibit the invasion of the trophoblast-like cell line HTR-8/SVneo through TNF-α, whereas nonactivated peripheral blood Mϕs had no effect on trophoblast invasion.[81] A preliminary study has reported that dMϕs isolated from high-risk early pregnancy women secreted lower levels of IL-1β and TNF-α than those in low-risk early pregnancy women.[82]

In the pathological pregnancy conditions, aberrantly activated Mϕs are capable of producing various molecules, such as TNF-α, nitric oxide (NO), and TGF-β, which may affect trophoblast invasion.[83] When activated by type-1 stimuli, Mϕs may increase the production of inducible NO synthase and subsequently promote the generation of NO.[84] Mϕ-derived NO will significantly reduce trophoblast invasiveness in vitro, while the levels of urokinase plasminogen activator receptor on the surface of trophoblast cells will decrease.[84],[85]

Previous studies have shown that dMϕs may act as important regulators of the number and differentiation of dNK cells through the production of IL-15[86] which could further induce the differentiation of resting endometrial NK cells into activated dNK cells.[86] Meanwhile, the interaction between dNK cells and dMϕ cells stimulates dNK cells to release IFN-γ which, in turn, induces the upregulation of IDO in dMϕs.[87] An in vitro study suggested that dNK cells could modulate CD14+ dMϕs to expand regulatory T (Treg)-cells. In addition, human EVT may redirect the monocyte-to-DC transition and induce regulatory DCs,[88] as well as induce monocyte differentiation into CD14+/CD16+ Mϕs.[89] Human trophoblasts also inhibit neutrophil extracellular trap formation and enhance apoptosis through vasoactive intestinal peptide-mediated pathways.[90]

In a word, the understanding how dMϕs participate in the maintenance of fetal–placental tolerance would lead to a better understanding how the innate immunity regulates both itself and the adaptive immunity to induce tolerance to nonself but nonpathogenic antigens.

  Dendritic Cells Top

In humans, mature myeloid DCs, such as CD83+ cells, are present in the first-trimester decidua with a density of 1–5 cells/mm 2.[91],[92],[93] In addition, immature DCs identified as CD205+ cells are present at a density of 2 cells/mm 2.[92] However, the total number of both mature and immature DCs is far less than the number of dMϕs. Meanwhile, other earlier research reported findings on alternative marker expression profiles of myeloid DCs within the decidua.[94],[95],[96] There is a teleological reason for low decidual DC (dDC) densities that the smaller number of DCs within a tissue, the lower ability to initiate adaptive T-cell responses in the draining lymph nodes.[97] In addition, this limited contact may retain the immune responsiveness when uterine mucosa is infected by pathogens and initiate the type 2 helper T-cell (Th2) immunity in the uterine microenvironment.[98]

Moreover, dDCs, analogously to dNK cells and dMϕ cells, have been reported to play a role in decidual tissue remodeling. Previous studies found that depletion of DCs in the peri-implantation period inhibited decidualization [99],[100] in a T-cell-independent manner. In addition, decidual angiogenesis is altered in DC-ablated mice, which has been mainly ascribed to a role of DCs in dNK cell differentiation or survival and a loss of DC-derived soluble Flt1.[99],[101] On the other hand, mice are genetically deficient in the key DC growth factor Flt3L; however, this condition has not resulted in obvious reproductive deficits.[75] Therefore, the contribution of DCs to decidualization remains controversial. Of note, CD14+ dMϕs are also suggested as a potential pool of DC progenitors, because once treated with combined IL-1β, TNF-α, IL-6, and PGE2, CD14+ dMϕ cells will generate cells with increased CD83 expression and will be equipped with the ability to stimulate T-cell proliferation, which is similar to those cytokine-simulated and peripheral blood monocyte-derived DCs.[49] These results suggest that dMϕ cells have the potential to convert to DC-like cells. Moreover, our recent studies have found that human thymic stromal lymphopoietin (TSLP) or supernatants from human trophoblasts specifically stimulate dDCs to highly produce abundant IL-10 and Th2-attracting chemokine CCL-17. The TSLP-activated dDCs prime decidual CD4+ T-cells to Th2 cell differentiation. Therefore, dDCs instructed by trophoblasts with the secretion of TSLP may induce Treg (H) 2 bias in human early pregnancy and further contribute to maternal–fetal immunotolerance.[100]

  Decidual T-Cells Top

Accounting for 10%–20% of decidual immune cells, CD3+ T-cells include 45%–70% of CD8+ T-cells, 40% of which encompass the effect/memory CD28 phenotype. CD4+ T-cells occupy 30%–45%, approximately 50% of which have the active/memory CD25dim phenotype, and CD25bright Foxp3+ Treg cells, TH1 cells, Th2 cells, and Th17 cells account for 5%, 5%–30%, 5%, and 2%, respectively. γδT cells, NKT cells, and CD4 CD8 TCRαβ T-cells are rare in decidua.[102],[103],[104],[105],[106] However, the majority of CD8+ and CD4+ T-cells found in the decidua show an induced Treg cell phenotype.

Mice with T-cell defects are fertile. At present, the function of decidual T-cells is largely unclear. Currently, it is known that Th1, Th2, and Th17 cells are the three main effector CD4 T-cell subsets, which are defined by the transcription factors they respectively expressed as to maintain their differentiated state and by the set of cytokines they expressed that mediate their effector functions.[107]

TH1 cells express the transcription factors T-bet and STAT4 and secrete IFN-γ as their signature cytokine, primarily promoting the eradication of virus-infected cells and intracellular pathogens within peripheral tissues. In addition, they also express the chemokine receptors CXCR3 (the receptor for CXCL9 [MIG], CXCL10 [IP-10], and CXCL11 [I-TAC]) and CCR5 (a receptor for CCL5 [RANTES]).[108] TH1 cells promote Mϕ activation as well as the expression of the CXCL9, CXCL10, and CXCL11 of the stromal and endothelial cells through the production of IFN-γ, which suggests that activated TH1 cells can promote both their own recruitment as well as the recruitment of the CXCR3+ CTLs.[108] TH1 cells also produce the TNF-α, which further promotes inflammation in a variety of ways. Notably, TH1 cells are the primary CD4+ T-cells that drive surgical allograft rejection. Therefore, they have long been considered as a major threat to fetal survival and potential contributors to pregnancy pathology.

Through regulation of antibody isotype switching and in the eradication of parasites, Th2 cells primarily play a role in allergic reactions. They express the transcription factors GATA3 and STAT6 and secrete the cytokines IL-4, IL-5, and IL-10. Th2 cells also preferentially express the chemokine receptor CCR4, which is required for migration to sites of allergic inflammation such as the airways. In pregnancy, in comparison to TH1 cells, Th2 cells has provided an alternative, less potentially embryo-toxic differentiation state for CD4+ T-cells, as well as the ability of Th2 cytokines to repress TH1 cell differentiation and function in trans.[52] Therefore, it is suggested that the maternal–fetal interface would involve a general Th2-bias of the T-cell response to minimize the generation of TH1 cells.[52]

TH17 cells express the transcription factors RORγt, STAT3, and IRF4, and secrete members of the IL-17 family of pro-inflammatory cytokines (most notably IL-17A). This type of cells can enhance acute inflammatory responses and regulate host immunity against extracellular bacteria and fungi. IL-17A can further induce epithelial cells to produce neutrophil chemoattractants such as CXCL1, and neutrophil survival factors such as G-CSF.[107] Whereas epithelial cells attract TH17 cells which express the predominant chemokine receptor CCR6 through the expression of ligand CCL20 on the surface. As the most recently described TH cell subset, the role of TH17 cells in reproduction is only now beginning to be elucidated.

CTLs, as the CD8+ T-cell counterparts of effector TH1 cells, mainly function in virus and intracellular pathogen clearance, which is similar to the activities of TH1 cells. In addition, CTLs also act in graft rejection and were considered direct threats to fetal survival previously. However, this view has been tempered, because recent studies have shown that the set of classical MHC-I molecules expressed on invasive trophoblasts was limited in both mouse and human,[105],[109] meaning that there is less opportunity for CTLs to directly attack the placenta. On the other hand, CD8+ T-cells can be induced to produce IFN-γ in a TCR-independent manner by the cytokines IL-12 and IL-18 produced by DCs and Mϕs.[110] Therefore, the mere presence of these cells at the maternal–fetal interface has in principle the potential to augment the detriment of pregnancy success.

  Regulatory T-Cells Top

Treg cells in pregnancy were initially reported to be increased in blood during the pregnancy of human and mouse [111],[112] and were required to prevent pregnancy failure in mice in allogeneic mating combinations.[111] Furthermore, our previous study has demonstrated that embryonic trophoblasts could induce decidual Treg cell differentiation and maintain maternal–fetal tolerance through TSLP instructing DCs.[113]

A series evidences have reported the relationship between PE and spontaneous abortion with decreased proportions of decidual Treg cells,[114],[115] spontaneous abortion with elevated proportions of decidual Th17 cells,[91] and RSA with increased decidual Th1/Th2 ratios.[92],[93] Excessive Th17 cell presence in spontaneous abortion cases has been linked to the pathogenesis of spontaneous abortion.[52],[116] Moreover, recent research in both mice and humans [117] has suggested that dNK cells are also capable of suppressing decidual Th17 cell accumulation through the production of IFN-γ. Therefore, elevated decidual Th17 cell frequencies have also been linked to low NK cell numbers in spontaneous abortion.[117]

Our studies and other researchers have shown that trophoblasts secreted cytokines and regulated the function and differentiation of decidual immune cells, which may further induce epigenetic changes in DSCs, consequently inhibiting their capacity to produce chemokines responsible for T-cell recruitment. For instance, our studies have found that DSC-derived IL-33 contributed to Th2 bias and inhibited decidual NK cell cytotoxicity through nuclear factor-B signaling in human early pregnancy.[118] CCL2 secreted by DSCs induced and maintained decidual leukocytes into Th2 bias in human early pregnancy.[119] In addition, Tim-3 protected DSCs from toll-like receptor-mediated apoptosis and inflammatory reactions and promoted Th2 bias at the maternal-fetal interface.[120] Our team has also found that programmed cell death-1 and Tim-3 pathways were associated with regulatory CD8+ T-cell function in decidua and maintenance of normal pregnancy,[121] and can also regulate CD4+ T-cells to induce Th2 bias at the maternal–fetal interface.[122] The decidual γδT cells, as a potential regulator for Th2 bias at the maternal–fetal interface, can promote trophoblast cell proliferation and invasion as well as suppress apoptosis by synthesizing IL-10.[123] In addition, our recent study has demonstrated that TSLP secreted by human trophoblasts can inhibit decidual γδ T-cell apoptosis by activating the STAT3 pathway and consequently downregulating caspase-3 expression.[124] Given the well-known immunosuppressive functions, Treg cells might be assumed to also generally limit decidual inflammation through antigen nonspecific mechanisms, which was consistent with the cell secretion of anti-inflammatory factors, such as IL-10 and TGF-β.[125]

Indeed, to balance the competing demands of reproduction and host defense, fully understanding the behavior of decidual T-cell behavior is a critical challenge and the research needs to focus on the biology of decidual T-cells.

  Prospective View Top

The cross talk at the fetal-maternal interface upholds the cytotoxic function of immune cells under strict control during healthy pregnancy. From an immunological perspective, the decidua has involved to encompass several advantages that optimize its role in reproduction. First, it contains a few resident leukocyte populations with a high degree of specialized functions, such as CD56bright NK cells and M2 Mϕs. The second is its ability to restrict the accumulation of certain immune cell types, including Th1 cells and CTLs, which are otherwise capable of promiscuously homing throughout peripheral tissues.

On the other hand, although only a few studies have shown the existence of TLR2 and TLR4 in human decidua cells,[126] Krikun et al.[127] have reported that LPS stimulation induces the secretion of IL-6 and IL-8 in human endometrial cell culture. Thus, we cannot rule out that bacterial infection stimulates TLR2/4 in decidual cells during pregnancy and further activates the downstream signaling to induce cytokine production. Then, the endogenous lipid ligands for TLR2/4 present on DSCs may change the characteristic of themselves and other associated cells during decidualization.[6] The mechanism for the regulation of cytokine secretion by DSCs requires further investigation.

Together, it is suggested that all the general developmental programs operate within DSCs to coordinate multiple aspects of decidual immunology. Although the molecular components of such programs remain largely unknown, we can deduce that the abnormality of the maternal immune system might lead to human pregnancy complications, and such disruptions may include a genetic, epigenetic, or environmental origin.

Given the importance of decidual immunology for embryo development and placental function and increasingly recognized long-term influence of maternal-fetal interface on human health, further research needs to gain an insight into the immunological properties of the decidua, and DSCs in particular, which is likely to be a major impact on human health. Moreover, it is also helpful for the development of therapeutics and/or therapeutic strategies to alleviate human auto- and allo-immune diseases/complications.

Financial support and sponsorship

This study was supported by the National Basic Research Program of China (2015CB943300), the Major Research Program of the National Natural Science Foundation of China (NSFC) (8149044, 81471548, and 31671200), the Oriented Project of Science and Technology Innovation from the Key Laboratory of Reproduction Regulation of NPFPC, and the Program for Zhuoxue of Fudan University, China.

Conflicts of interest

There are no conflicts of interest.

  References Top

Erlebacher A. Immunology of the maternal-fetal interface. Annu Rev Immunol 2013;31:387-411. doi: 10.1146/annurev-immunol-032712-100003.  Back to cited text no. 1
Arck PC, Hecher K. Fetomaternal immune cross-talk and its consequences for maternal and offspring's health. Nat Med 2013;19:548-56. doi: 10.1038/nm.3160.  Back to cited text no. 2
Hsu P, Nanan RK. Innate and adaptive immune interactions at the fetal-maternal interface in healthy human pregnancy and pre-eclampsia. Front Immunol 2014;5:125. doi: 10.3389/fimmu.2014.00125.  Back to cited text no. 3
Fu B, Tian Z, Wei H. TH17 cells in human recurrent pregnancy loss and pre-eclampsia. Cell Mol Immunol 2014;11:564-70. doi: 10.1038/cmi.2014.54.  Back to cited text no. 4
Fu B, Wei H. Decidual natural killer cells and the immune microenvironment at the maternal-fetal interface. Sci China Life Sci 2016;59:1224-31. doi: 10.1007/s11427-016-0337-1.  Back to cited text no. 5
Mori M, Bogdan A, Balassa T, Csabai T, Szekeres-Bartho J. The decidua-the maternal bed embracing the embryo-maintains the pregnancy. Semin Immunopathol 2016;38:635-49. doi: 10.1007/s00281-016-0574-0.  Back to cited text no. 6
Nancy P, Tagliani E, Tay CS, Asp P, Levy DE, Erlebacher A. Chemokine gene silencing in decidual stromal cells limits T cell access to the maternal-fetal interface. Science 2012;336:1317-21. doi: 10.1126/science.1220030.  Back to cited text no. 7
Sharma S, Godbole G, Modi D. Decidual control of trophoblast invasion. Am J Reprod Immunol 2016;75:341-50. doi: 10.1111/aji.12466.  Back to cited text no. 8
Hess AP, Hamilton AE, Talbi S, Dosiou C, Nyegaard M, Nayak N, et al. Decidual stromal cell response to paracrine signals from the trophoblast: Amplification of immune and angiogenic modulators. Biol Reprod 2007;76:102-17. doi: 10.1095/biolreprod.106.054791.  Back to cited text no. 9
Trundley A, Moffett A. Human uterine leukocytes and pregnancy. Tissue Antigens 2004;63:1-12. doi: 10.1111/j.1399-0039.2004.00170.x.  Back to cited text no. 10
Bulmer JN, Williams PJ, Lash GE. Immune cells in the placental bed. Int J Dev Biol 2010;54:281-94. doi: 10.1387/ijdb.082763jb.  Back to cited text no. 11
Bulmer JN, Lash GE. Human uterine natural killer cells: A reappraisal. Mol Immunol 2005;42:511-21. doi: 10.1016/j.molimm.2004.07.035.  Back to cited text no. 12
Kane N, Kelly R, Saunders PT, Critchley HO. Proliferation of uterine natural killer cells is induced by human chorionic gonadotropin and mediated via the mannose receptor. Endocrinology 2009;150:2882-8. doi: 10.1210/en.2008-1309.  Back to cited text no. 13
Vacca P, Moretta L, Moretta A, Mingari MC. Origin, phenotype and function of human natural killer cells in pregnancy. Trends Immunol 2011;32:517-23. doi: 10.1016/j.it.2011.06.013.  Back to cited text no. 14
Jabrane-Ferrat N, Siewiera J. The up side of decidual natural killer cells: New developments in immunology of pregnancy. Immunology 2014;141:490-7. doi: 10.1111/imm.12218.  Back to cited text no. 15
Carlino C, Stabile H, Morrone S, Bulla R, Soriani A, Agostinis C, et al. Recruitment of circulating NK cells through decidual tissues: A possible mechanism controlling NK cell accumulation in the uterus during early pregnancy. Blood 2008;111:3108-15. doi: 10.1182/blood-2007-08-105965.  Back to cited text no. 16
Eriksson M, Meadows SK, Wira CR, Sentman CL. Unique phenotype of human uterine NK cells and their regulation by endogenous TGF-beta. J Leukoc Biol 2004;76:667-75. doi: 10.1189/jlb.0204090.  Back to cited text no. 17
Keskin DB, Allan DS, Rybalov B, Andzelm MM, Stern JN, Kopcow HD, et al. TGFbeta promotes conversion of CD16+ peripheral blood NK cells into CD16-NK cells with similarities to decidual NK cells. Proc Natl Acad Sci U S A 2007;104:3378-83. doi: 10.1073/pnas.0611098104.  Back to cited text no. 18
Drake PM, Gunn MD, Charo IF, Tsou CL, Zhou Y, Huang L, et al. Human placental cytotrophoblasts attract monocytes and CD56(bright) natural killer cells via the actions of monocyte inflammatory protein 1alpha. J Exp Med 2001;193:1199-212. doi: 10.1084/jem.193.10.1199.  Back to cited text no. 19
Hanna J, Wald O, Goldman-Wohl D, Prus D, Markel G, Gazit R, et al. CXCL12 expression by invasive trophoblasts induces the specific migration of CD16-human natural killer cells. Blood 2003;102:1569-77. doi: 10.1182/blood-2003-02-0517.  Back to cited text no. 20
Kunkel EJ, Butcher EC. Chemokines and the tissue-specific migration of lymphocytes. Immunity 2002;16:1-4. doi: 10.1016/S1074-7613(01)00261-8.  Back to cited text no. 21
Cooper MA, Fehniger TA, Caligiuri MA. The biology of human natural killer-cell subsets. Trends Immunol 2001;22:633-40. doi: 10.1016/S1471-4906(01)02060-9.  Back to cited text no. 22
El Costa H, Casemayou A, Aguerre-Girr M, Rabot M, Berrebi A, Parant O, et al. Critical and differential roles of NKp46- and NKp30-activating receptors expressed by uterine NK cells in early pregnancy. J Immunol 2008;181:3009-17. doi: 10.4049/jimmunol.181.5.3009.  Back to cited text no. 23
Hanna J, Goldman-Wohl D, Hamani Y, Avraham I, Greenfield C, Natanson-Yaron S, et al. Decidual NK cells regulate key developmental processes at the human fetal-maternal interface. Nat Med 2006;12:1065-74. doi: 10.1038/nm1452.  Back to cited text no. 24
Ferlazzo G, Pack M, Thomas D, Paludan C, Schmid D, Strowig T, et al. Distinct roles of IL-12 and IL-15 in human natural killer cell activation by dendritic cells from secondary lymphoid organs. Proc Natl Acad Sci U S A 2004;101:16606-11. doi: 10.1073/pnas.0407522101.  Back to cited text no. 25
Hazan AD, Smith SD, Jones RL, Whittle W, Lye SJ, Dunk CE. Vascular-leukocyte interactions: Mechanisms of human decidual spiral artery remodeling in vitro. Am J Pathol 2010;177:1017-30. doi: 10.2353/ajpath.2010.091105.  Back to cited text no. 26
Le Bouteiller P, Siewiera J, Casart Y, Aguerre-Girr M, El Costa H, Berrebi A, et al. The human decidual NK-cell response to virus infection: What can we learn from circulating NK lymphocytes? J Reprod Immunol 2010;612:447-63. doi: 10.1016/j.jri.2010.12.005.  Back to cited text no. 27
Male V, Hughes T, McClory S, Colucci F, Caligiuri MA, Moffett A. Immature NK cells, capable of producing IL-22, are present in human uterine mucosa. J Immunol 2010;185:3913-8. doi: 10.4049/jimmunol.1001637.  Back to cited text no. 28
Vacca P, Pietra G, Falco M, Romeo E, Bottino C, Bellora F, et al. Analysis of natural killer cells isolated from human decidua: Evidence that 2B4 (CD244) functions as an inhibitory receptor and blocks NK-cell function. Blood 2006;108:4078-85. doi: 10.1182/blood-2006-04-017343.  Back to cited text no. 29
Kopcow HD, Allan DS, Chen X, Rybalov B, Andzelm MM, Ge B, et al. Human decidual NK cells form immature activating synapses and are not cytotoxic. Proc Natl Acad Sci U S A 2005;102:15563-8. doi: 10.1073/pnas.0507835102.  Back to cited text no. 30
El Costa H, Tabiasco J, Berrebi A, Parant O, Aguerre-Girr M, Piccinni MP, et al. Effector functions of human decidual NK cells in healthy early pregnancy are dependent on the specific engagement of natural cytotoxicity receptors. J Reprod Immunol 2009;82:142-7. doi: 10.1016/j.jri.2009.06.123.  Back to cited text no. 31
Deshmukh US, Bagavant H. When killers become helpers. Sci Transl Med 2007;28:201-6. doi: 10.1126/scitranslmed.3006850.  Back to cited text no. 32
Kalkunte SS, Mselle TF, Norris WE, Wira CR, Sentman CL, Sharma S. Vascular endothelial growth factor C facilitates immune tolerance and endovascular activity of human uterine NK cells at the maternal-fetal interface. J Immunol 2009;182:4085-92. doi: 10.4049/jimmunol.0803769.  Back to cited text no. 33
Moffett A, Hiby SE. How does the maternal immune system contribute to the development of pre-eclampsia? Placenta 2007;28 Suppl A:S51-6. doi: 10.1016/j.placenta.2006.11.008.  Back to cited text no. 34
Lash GE, Schiessl B, Kirkley M, Innes BA, Cooper A, Searle RF, et al. Expression of angiogenic growth factors by uterine natural killer cells during early pregnancy. J Leukoc Biol 2006;80:572-80. doi: 10.1189/jlb.0406250.  Back to cited text no. 35
Craven CM, Morgan T, Ward K. Decidual spiral artery remodelling begins before cellular interaction with cytotrophoblasts. Placenta 1998;19:241-52. doi: 10.1016/S0143-4004(98)90055-8.  Back to cited text no. 36
Matson BC, Caron KM. Uterine natural killer cells as modulators of the maternal-fetal vasculature. Int J Dev Biol 2014;58:199-204. doi: 10.1387/ijdb.140032kc.  Back to cited text no. 37
Fraser R, Whitley GS, Johnstone AP, Host AJ, Sebire NJ, Thilaganathan B, et al. Impaired decidual natural killer cell regulation of vascular remodelling in early human pregnancies with high uterine artery resistance. J Pathol 2012;228:322-32. doi: 10.1002/path.4057.  Back to cited text no. 38
Hiby SE, Apps R, Sharkey AM, Farrell LE, Gardner L, Mulder A, et al. Maternal activating KIRs protect against human reproductive failure mediated by fetal HLA-C2. J Clin Invest 2010;120:4102-10. doi: 10.1172/JCI43998.  Back to cited text no. 39
Hiby SE, Ashrafian-Bonab M, Farrell L, Single RM, Balloux F, Carrington M, et al. Distribution of killer cell immunoglobulin-like receptors (KIR) and their HLA-C ligands in two Iranian populations. Immunogenetics 2010;62:65-73. doi: 10.1007/s00251-009-0408-5.  Back to cited text no. 40
Eskicioglu F, ízdemir AT, ízdemir RB, Turan GA, Akan Z, Hasdemir SP. The association of HLA-G and immune markers in recurrent miscarriages. J Matern Fetal Neonatal Med 2016;29:3056-60. doi: 10.3109/14767058.2015.1114085.  Back to cited text no. 41
Ashkar AA, Di Santo JP, Croy BA. Interferon gamma contributes to initiation of uterine vascular modification, decidual integrity, and uterine natural killer cell maturation during normal murine pregnancy. J Exp Med 2000;192:259-70. doi: 10.1084/jem.192.2.259.  Back to cited text no. 42
Barber EM, Pollard JW. The uterine NK cell population requires IL-15 but these cells are not required for pregnancy nor the resolution of a Listeria monocytogenes infection. J Immunol 1986;164:956-61. doi: 10.4049/jimmunol.171.1.37.  Back to cited text no. 43
Sun J, Yang M, Ban Y, Gao W, Song B, Wang Y, et al. Tim-3 is upregulated in NK cells during early pregnancy and inhibits NK cytotoxicity toward trophoblast in galectin-9 dependent pathway. PLoS One 2016;11:e0147186. doi: 10.1371/journal.pone.0147186.  Back to cited text no. 44
Li YH, Zhou WH, Tao Y, Wang SC, Jiang YL, Zhang D, et al. The Galectin-9/Tim-3 pathway is involved in the regulation of NK cell function at the maternal-fetal interface in early pregnancy. Cell Mol Immunol 2016;13:73-81. doi: 10.1038/cmi.2014.126.  Back to cited text no. 45
Ophir Y, Duev-Cohen A, Yamin R, Tsukerman P, Bauman Y, Gamliel M, et al. PILRa binds an unknown receptor expressed primarily on CD56bright and decidual-NK cells and activates NK cell functions. Oncotarget 2016;7:40953-64. doi: 10.18632/oncotarget.8397.  Back to cited text no. 46
Faust Z, Laskarin G, Rukavina D, Szekeres-Bartho J. Progesterone-induced blocking factor inhibits degranulation of natural killer cells. Am J Reprod Immunol 1999;42:71-5.  Back to cited text no. 47
Bogdan A, Berta G, Szekeres-Bartho J. PIBF positive uterine NK cells in the mouse decidua. J Reprod Immunol 2017;119:38-43. doi: 10.1016/j.jri.2016.12.001.  Back to cited text no. 48
Kämmerer U, Eggert AO, Kapp M, McLellan AD, Geijtenbeek TB, Dietl J, et al. Unique appearance of proliferating antigen-presenting cells expressing DC-SIGN (CD209) in the decidua of early human pregnancy. Am J Pathol 2003;162:887-96. doi: 10.1016/S0002-9440(10)63884-9.  Back to cited text no. 49
Vacca P, Cantoni C, Vitale M, Prato C, Canegallo F, Fenoglio D, et al. Crosstalk between decidual NK and CD14+ myelomonocytic cells results in induction of Tregs and immunosuppression. Proc Natl Acad Sci U S A 2010;107:11918-23. doi: 10.1073/pnas.1001749107.  Back to cited text no. 50
Quack KC, Vassiliadou N, Pudney J, Anderson DJ, Hill JA. Leukocyte activation in the decidua of chromosomally normal and abnormal fetuses from women with recurrent abortion. Hum Reprod 2001;16:949-55. doi: 10.1093/humrep/16.5.949.  Back to cited text no. 51
Saito S, Nakashima A, Shima T, Ito M. Th1/Th2/Th17 and regulatory T-cell paradigm in pregnancy. Am J Reprod Immunol 2010;63:601-10. doi: 10.1111/j.1600-0897.2010.00852.x.  Back to cited text no. 52
Wallace AE, Fraser R, Cartwright JE. Extravillous trophoblast and decidual natural killer cells: A remodelling partnership. Hum Reprod Update 2012;18:458-71. doi: 10.1093/humupd/dms015.  Back to cited text no. 53
Ziegler-Heitbrock L, Ancuta P, Crowe S, Dalod M, Grau V, Hart DN, et al. Nomenclature of monocytes and dendritic cells in blood. Blood 2010;116:e74-80. doi: 10.1182/blood-2010-02-258558.  Back to cited text no. 54
Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol 2005;5:953-64. doi: 10.1038/nri1733.  Back to cited text no. 55
Haldar M, Murphy KM. Origin, development, and homeostasis of tissue-resident macrophages. Immunol Rev 2014;262:25-35. doi: 10.1111/imr.12215.  Back to cited text no. 56
Nahrendorf M, Swirski FK. Monocyte and macrophage heterogeneity in the heart. Circ Res 2013;112:1624-33. doi: 10.1161/CIRCRESAHA.113.300890.  Back to cited text no. 57
Care AS, Diener KR, Jasper MJ, Brown HM, Ingman WV, Robertson SA. Macrophages regulate corpus luteum development during embryo implantation in mice. J Clin Invest 2013;123:3472-87. doi: 10.1172/JCI60561.  Back to cited text no. 58
Bulmer JN, Morrison L, Longfellow M, Ritson A, Pace D. Granulated lymphocytes in human endometrium: Histochemical and immunohistochemical studies. Hum Reprod 1991;6:791-8. doi: 10.1093/oxfordjournals.humrep.a137430.  Back to cited text no. 59
Jones RL, Hannan NJ, Kaitu'u TJ, Zhang J, Salamonsen LA. Identification of chemokines important for leukocyte recruitment to the human endometrium at the times of embryo implantation and menstruation. J Clin Endocrinol Metab 2004;89:6155-67. doi: 10.1210/jc.2004-0507.  Back to cited text no. 60
Bulmer JN, Morrison L, Smith JC. Expression of class II MHC gene products by macrophages in human uteroplacental tissue. Immunology 1988;63:707-14.  Back to cited text no. 61
Lessin DL, Hunt JS, King CR, Wood GW. Antigen expression by cells near the maternal-fetal interface. Am J Reprod Immunol Microbiol 1988;63:707-14. doi: 10.1111/j.1600-0897.1988.tb00169.x.  Back to cited text no. 62
Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M. Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol 2013;229:176-85. doi: 10.1002/path.4133.  Back to cited text no. 63
Gustafsson C, Mjösberg J, Matussek A, Geffers R, Matthiesen L, Berg G, et al. Gene expression profiling of human decidual macrophages: Evidence for immunosuppressive phenotype. PLoS One 2008;3:e2078. doi: 10.1371/journal.pone.0002078.  Back to cited text no. 64
Laskarin G, Cupurdija K, Tokmadzic VS, Dorcic D, Dupor J, Juretic K, et al. The presence of functional mannose receptor on macrophages at the maternal-fetal interface. Hum Reprod 2005;20:1057-66. doi: 10.1093/humrep/deh740.  Back to cited text no. 65
Bürk MR, Troeger C, Brinkhaus R, Holzgreve W, Hahn S. Severely reduced presence of tissue macrophages in the basal plate of pre-eclamptic placentae. Placenta 2001;22:309-16. doi: 10.1053/plac.2001.0624.  Back to cited text no. 66
Soilleux EJ, Morris LS, Leslie G, Chehimi J, Luo Q, Levroney E, et al. Constitutive and induced expression of DC-SIGN on dendritic cell and macrophage subpopulations in situ and in vitr o. J Leukoc Biol 2002;71:445-57.  Back to cited text no. 67
Houser BL, Tilburgs T, Hill J, Nicotra ML, Strominger JL. Two unique human decidual macrophage populations. J Immunol 2011;186:2633-42. doi: 10.4049/jimmunol.1003153.  Back to cited text no. 68
Abrahams VM, Kim YM, Straszewski SL, Romero R, Mor G. Macrophages and apoptotic cell clearance during pregnancy. Am J Reprod Immunol 2004;51:275-82. doi: 10.1111/j.1600-0897.2004.00156.x.  Back to cited text no. 69
Han G, Chen G, Shen B, Li Y. Tim-3: An activation marker and activation limiter of innate immune cells. Front Immunol 2013;4:449. doi: 10.3389/fimmu.2013.00449.  Back to cited text no. 70
Svensson-Arvelund J, Ernerudh J. The role of macrophages in promoting and maintaining homeostasis at the fetal-maternal interface. Am J Reprod Immunol 2015;74:100-9. doi: 10.1111/aji.12357.  Back to cited text no. 71
Hamilton JA. Colony-stimulating factors in inflammation and autoimmunity. Nat Rev Immunol 2008;8:533-44. doi: 10.1038/nri2356.  Back to cited text no. 72
Abrahams VM, Visintin I, Aldo PB, Guller S, Romero R, Mor G. A role for TLRs in the regulation of immune cell migration by first trimester trophoblast cells. J Immunol 2005;175:8096-104. doi: 10.4049/jimmunol.175.12.8096.  Back to cited text no. 73
Pampfer S, Daiter E, Barad D, Pollard JW. Expression of the colony-stimulating factor-1 receptor (c-fms proto-oncogene product) in the human uterus and placenta. Biol Reprod 1992;46:48-57. doi: 10.1095/biolreprod46.1.48.  Back to cited text no. 74
Tagliani E, Shi C, Nancy P, Tay CS, Pamer EG, Erlebacher A. Coordinate regulation of tissue macrophage and dendritic cell population dynamics by CSF-1. J Exp Med 2011;208:1901-16. doi: 10.1084/jem.20110866.  Back to cited text no. 75
Svensson J, Jenmalm MC, Matussek A, Geffers R, Berg G, Ernerudh J. Macrophages at the fetal-maternal interface express markers of alternative activation and are induced by M-CSF and IL-10. J Immunol 2011;187:3671-82. doi: 10.4049/jimmunol.1100130.  Back to cited text no. 76
Lidström C, Matthiesen L, Berg G, Sharma S, Ernerudh J, Ekerfelt C. Cytokine secretion patterns of NK cells and macrophages in early human pregnancy decidua and blood: Implications for suppressor macrophages in decidua. Am J Reprod Immunol 2003;50:444-52. doi: 10.1046/j.8755-8920.2003.00112.x.  Back to cited text no. 77
Renaud SJ, Graham CH. The role of macrophages in utero-placental interactions during normal and pathological pregnancy. Immunol Invest 2008;37:535-64. doi: 10.1080/08820130802191375.  Back to cited text no. 78
Reister F, Frank HG, Kingdom JC, Heyl W, Kaufmann P, Rath W, et al. Macrophage-induced apoptosis limits endovascular trophoblast invasion in the uterine wall of preeclamptic women. Lab Invest 2001;81:1143-52. doi: 10.1038/labinvest.3780326.  Back to cited text no. 79
Mor G, Abrahams VM. Potential role of macrophages as immunoregulators of pregnancy. Reprod Biol Endocrinol 2003;1:119. doi: 10.1186/1477-7827-1-119.  Back to cited text no. 80
Renaud SJ, Postovit LM, Macdonald-Goodfellow SK, McDonald GT, Caldwell JD, Graham CH. Activated macrophages inhibit human cytotrophoblast invasiveness in vitro. Biol Reprod 2005;73:237-43. doi: 10.1095/biolreprod.104.038000.  Back to cited text no. 81
Lash GE, Burton GJ, Chamley LW, Clifton VL, Constancia M, Crocker IP, et al. IFPA Meeting 2009 workshops report. Placenta 2010;31:S4-20. doi: 10.1016/j.placenta.2009.12.008.  Back to cited text no. 82
Wilczynski JR, Tchórzewski H, Glowacka E, Banasik M, Lewkowicz P, Szpakowski M, et al. Cytokine secretion by decidual lymphocytes in transient hypertension of pregnancy and pre-eclampsia. Mediators Inflamm 2002;11:105-11. doi: 10.1080/09629350220131962.  Back to cited text no. 83
Pathak N, Sawhney H, Vasishta K, Majumdar S. Estimation of oxidative products of nitric oxide (nitrates, nitrites) in preeclampsia. Aust N Z J Obstet Gynaecol 1999;39:484-7. doi: 10.1111/j.1479-828X.1999.tb03139.x.  Back to cited text no. 84
Postovit LM, Adams MA, Graham CH. Does nitric oxide play a role in the aetiology of pre-eclampsia? Placenta 2001;22 Suppl A:S51-5. doi: 10.1053/plac.2001.0636.  Back to cited text no. 85
Manaster I, Mizrahi S, Goldman-Wohl D, Sela HY, Stern-Ginossar N, Lankry D, et al. Endometrial NK cells are special immature cells that await pregnancy. J Immunol 2008;181:1869-76. doi: 10.4049/jimmunol.181.3.1869.  Back to cited text no. 86
Tang MX, Hu XH, Liu ZZ, Kwak-Kim J, Liao AH. What are the roles of macrophages and monocytes in human pregnancy? J Reprod Immunol 2015;112:73-80. doi: 10.1016/j.jri.2015.08.001.  Back to cited text no. 87
Zhao L, Shao Q, Zhang Y, Zhang L, He Y, Wang L, et al. Human monocytes undergo functional re-programming during differentiation to dendritic cell mediated by human extravillous trophoblasts. Sci Rep 2016;6:20409. doi: 10.1038/srep20409.  Back to cited text no. 88
Aldo PB, Racicot K, Craviero V, Guller S, Romero R, Mor G. Trophoblast induces monocyte differentiation into CD14+/CD16+ macrophages. Am J Reprod Immunol 2014;72:270-84. doi: 10.1111/aji.12288.  Back to cited text no. 89
Calo G, Sabbione F, Vota D, Paparini D, Ramhorst R, Trevani A, et al. Trophoblast cells inhibit neutrophil extracellular trap formation and enhance apoptosis through vasoactive intestinal peptide-mediated pathways. Hum Reprod 2017;32:55-64. doi: 10.1093/humrep/dew292.  Back to cited text no. 90
Kämmerer U, Schoppet M, McLellan AD, Kapp M, Huppertz HI, Kämpgen E, et al. Human decidua contains potent immunostimulatory CD83(+) dendritic cells. Am J Pathol 2000;157:159-69. doi: 10.1016/S0002-9440(10)64527-0.  Back to cited text no. 91
Rieger L, Honig A, Sütterlin M, Kapp M, Dietl J, Ruck P, et al. Antigen-presenting cells in human endometrium during the menstrual cycle compared to early pregnancy. J Soc Gynecol Investig 2004;11:488-93. doi: 10.1016/j.jsgi.2004.05.007.  Back to cited text no. 92
Kemp B, Schmitz S, Krusche CA, Rath W, von Rango U. Dendritic cells are equally distributed in intrauterine and tubal ectopic pregnancies. Fertil Steril 2011;95:28-32. doi: 10.1016/j.fertnstert.2010.05.045.  Back to cited text no. 93
Ban YL, Kong BH, Qu X, Yang QF, Ma YY. BDCA-1+, BDCA-2+ and BDCA-3+ dendritic cells in early human pregnancy decidua. Clin Exp Immunol 2008;151:399-406. doi: 10.1111/j.1365-2249.  Back to cited text no. 94
Miyazaki S, Tsuda H, Sakai M, Hori S, Sasaki Y, Futatani T, et al. Predominance of Th2-promoting dendritic cells in early human pregnancy decidua. J Leukoc Biol 2003;74:514-22. doi: 10.1189/jlb.1102566.  Back to cited text no. 95
Gardner L, Moffett A. Dendritic cells in the human decidua. Biol Reprod 2003;69:1438-46. doi: 10.1095/biolreprod.103.017574.  Back to cited text no. 96
Tagliani E, Erlebacher A. Dendritic cell function at the maternal-fetal interface. Expert Rev Clin Immunol 2011;7:593-602. doi: 10.1586/eci.11.52.  Back to cited text no. 97
Tannetta D, Dragovic R, Alyahyaei Z, Southcombe J. Extracellular vesicles and reproduction-promotion of successful pregnancy. Cell Mol Immunol 2014;11:548-63. doi: 10.1038/cmi.2014.42.  Back to cited text no. 98
Krey G, Frank P, Shaikly V, Barrientos G, Cordo-Russo R, Ringel F, et al. In vivo dendritic cell depletion reduces breeding efficiency, affecting implantation and early placental development in mice. J Mol Med (Berl) 2008;86:999-1011. doi: 10.1007/s00109-008-0379-2.  Back to cited text no. 99
Guo PF, Du MR, Wu HX, Lin Y, Jin LP, Li DJ. Thymic stromal lymphopoietin from trophoblasts induces dendritic cell-mediated regulatory TH2 bias in the decidua during early gestation in humans. Blood 2010;116:2061-9. doi: 10.1182/blood-2009-11-252940.  Back to cited text no. 100
Plaks V, Birnberg T, Berkutzki T, Sela S, BenYashar A, Kalchenko V, et al. Uterine DCs are crucial for decidua formation during embryo implantation in mice. J Clin Invest 2008;118:3954-65. doi: 10.1172/JCI36682.  Back to cited text no. 101
Tilburgs T, van der Mast BJ, Nagtzaam NM, Roelen DL, Scherjon SA, Claas FH. Expression of NK cell receptors on decidual T cells in human pregnancy. J Reprod Immunol 2009;80:22-32. doi: 10.1016/j.jri.2009.02.004.  Back to cited text no. 102
Tilburgs T, Claas FH, Scherjon SA. Elsevier trophoblast research award lecture: Unique properties of decidual T cells and their role in immune regulation during human pregnancy. Placenta 2010;31:S82-6. doi: 10.1016/j.placenta.2010.01.007.  Back to cited text no. 103
Dimova T, Nagaeva O, Stenqvist AC, Hedlund M, Kjellberg L, Strand M, et al. Maternal Foxp3 expressing CD4+ CD25+ and CD4+ CD25- regulatory T-cell populations are enriched in human early normal pregnancy decidua: A phenotypic study of paired decidual and peripheral blood samples. Am J Reprod Immunol 2011;66 Suppl 1:44-56. doi: 10.1111/j.1600-0897.2011.01046.x.  Back to cited text no. 104
Marlin R, Nugeyre MT, Duriez M, Cannou C, Le Breton A, Berkane N, et al. Decidual soluble factors participate in the control of HIV-1 infection at the maternofetal interface. Retrovirology 2011;8:58. doi: 10.1186/1742-4690-8-58.  Back to cited text no. 105
Mjösberg J, Berg G, Jenmalm MC, Ernerudh J. FOXP3 regulatory T cells and T helper 1, T helper 2, and T helper 17 cells in human early pregnancy decidua. Biol Reprod 2010;82:698-705. doi: 10.1095/biolreprod.109.081208.  Back to cited text no. 106
Nancy P, Erlebacher A. T cell behavior at the maternal-fetal interface. Int J Dev Biol 2014;58:189-98. doi: 10.1387/ijdb.140054ae.  Back to cited text no. 107
Nakanishi Y, Lu B, Gerard C, Iwasaki A. CD8(+) T lymphocyte mobilization to virus-infected tissue requires CD4(+) T-cell help. Nature 2009;462:510-3. doi: 10.1038/nature08511.  Back to cited text no. 108
King A, Burrows TD, Hiby SE, Bowen JM, Joseph S, Verma S, et al. Surface expression of HLA-C antigen by human extravillous trophoblast. Placenta 2000;21:376-87. doi: 10.1053/plac.1999.0496.  Back to cited text no. 109
Freeman BE, Hammarlund E, Raué HP, Slifka MK. Regulation of innate CD8+ T-cell activation mediated by cytokines. Proc Natl Acad Sci U S A 2012;109:9971-6. doi: 10.1073/pnas.1203543109.  Back to cited text no. 110
Aluvihare VR, Kallikourdis M, Betz AG. Regulatory T cells mediate maternal tolerance to the fetus. Nat Immunol 2004;5:266-71. doi: 10.1038/ni1037.  Back to cited text no. 111
Nakashima A, Ito M, Shima T, Bac ND, Hidaka T, Saito S. Accumulation of IL-17-positive cells in decidua of inevitable abortion cases. Am J Reprod Immunol 2010;64:4-11. doi: 10.1111/j.1600-0897.2010.00812.x.  Back to cited text no. 112
Du MR, Guo PF, Piao HL, Wang SC, Sun C, Jin LP, et al. Embryonic trophoblasts induce decidual regulatory T cell differentiation and maternal-fetal tolerance through thymic stromal lymphopoietin instructing dendritic cells. J Immunol 2014;192:1502-11. doi: 10.4049/jimmunol.1203425.  Back to cited text no. 113
Sasaki Y, Darmochwal-Kolarz D, Suzuki D, Sakai M, Ito M, Shima T, et al. Proportion of peripheral blood and decidual CD4(+) CD25(bright) regulatory T cells in pre-eclampsia. Clin Exp Immunol 2007;149:139-45. doi: 10.1111/j.1365-2249.2007.03397.x.  Back to cited text no. 114
Sasaki Y, Sakai M, Miyazaki S, Higuma S, Shiozaki A, Saito S. Decidual and peripheral blood CD4+ CD25+ regulatory T cells in early pregnancy subjects and spontaneous abortion cases. Mol Hum Reprod 2004;10:347-53. doi: 10.1093/molehr/gah044.  Back to cited text no. 115
Mao G, Wang J, Kang Y, Tai P, Wen J, Zou Q, et al. Progesterone increases systemic and local uterine proportions of CD4+ CD25+ Treg cells during midterm pregnancy in mice. Endocrinology 2010;151:5477-88. doi: 10.1210/en.2010-0426.  Back to cited text no. 116
Fu B, Li X, Sun R, Tong X, Ling B, Tian Z, et al. Natural killer cells promote immune tolerance by regulating inflammatory TH17 cells at the human maternal-fetal interface. Proc Natl Acad Sci U S A 2013;110:E231-40. doi: 10.1073/pnas.1206322110.  Back to cited text no. 117
Hu WT, Huang LL, Li MQ, Jin LP, Li DJ, Zhu XY. Decidual stromal cell-derived IL-33 contributes to Th2 bias and inhibits decidual NK cell cytotoxicity through NF-κB signaling in human early pregnancy. J Reprod Immunol 2015;109:52-65. doi: 10.1016/j.jri.2015.01.004.  Back to cited text no. 118
He YY, He XJ, Guo PF, Du MR, Shao J, Li MQ, et al. The decidual stromal cells-secreted CCL2 induces and maintains decidual leukocytes into Th2 bias in human early pregnancy. Clin Immunol 2012;145:161-73. doi: 10.1016/j.clim.2012.07.017.  Back to cited text no. 119
Wang S, Cao C, Piao H, Li Y, Tao Y, Zhang X, et al. Tim-3 protects decidual stromal cells from toll-like receptor-mediated apoptosis and inflammatory reactions and promotes Th2 bias at the maternal-fetal interface. Sci Rep 2015;5:9013. doi: 10.1038/srep09013.  Back to cited text no. 120
Wang SC, Li YH, Piao HL, Hong XW, Zhang D, Xu YY, et al. PD-1 and Tim-3 pathways are associated with regulatory CD8 T-cell function in decidua and maintenance of normal pregnancy. Cell Death Dis 2015;6:e1738. doi: 10.1038/cddis.2015.112.  Back to cited text no. 121
Wang S, Zhu X, Xu Y, Zhang D, Li Y, Tao Y, et al. Programmed cell death-1 (PD-1) and T-cell immunoglobulin mucin-3 (Tim-3) regulate CD4+ T cells to induce type 2 helper T cell (Th2) bias at the maternal-fetal interface. Hum Reprod 2016;31:700-11. doi: 10.1093/humrep/dew019.  Back to cited text no. 122
Fan DX, Duan J, Li MQ, Xu B, Li DJ, Jin LP. The decidual gamma-delta T cells up-regulate the biological functions of trophoblasts via IL-10 secretion in early human pregnancy. Clin Immunol 2011;141:284-92. doi: 10.1016/j.clim.2011.07.008.  Back to cited text no. 123
Duan J, Jiang XP, Li MQ, Fan DX, Wang Y, Li DJ, et al. Thymic stromal lymphopoietin suppresses the apoptosis of decidual gamma-delta T cells via regulation of the signal transduction and activation of transcription 3/caspase-3 signaling pathway. Am J Reprod Immunol 2013;70:464-71. doi: 10.1111/aji.12158.  Back to cited text no. 124
Ernerudh J, Berg G, Mjösberg J. Regulatory T helper cells in pregnancy and their roles in systemic versus local immune tolerance. Am J Reprod Immunol 2011;66 Suppl 1:31-43. doi: 10.1111/j.1600-0897.2011.01049.x.  Back to cited text no. 125
Krikun G, Lockwood CJ, Abrahams VM, Mor G, Paidas M, Guller S. Expression of toll-like receptors in the human decidua. Histol Histopathol 2007;22:847-54. doi: 10.14670/HH-22.847.  Back to cited text no. 126
Krikun G, Trezza J, Shaw J, Rahman M, Guller S, Abrahams VM, et al. Lipopolysaccharide appears to activate human endometrial endothelial cells through TLR-4-dependent and TLR-4-independent mechanisms. Am J Reprod Immunol 2012;68:233-7. doi: 10.1111/j.1600-0897.2012.01164.x.  Back to cited text no. 127


Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  In this article
Decidual Macroph...
Dendritic Cells
Decidual T-Cells
Regulatory T-Cells
Prospective View
Decidual Natural...

 Article Access Statistics
    PDF Downloaded428    
    Comments [Add]    

Recommend this journal