5/15/24, 10:36 AM Immunology of the maternal-fetal interface - UpToDate || U TO Date7 Official reprint from UpToDate® p www.uptodate.com © 2024 UpToDate, Inc and/or its affiliates All Rights Reserved ® Immunology of the maternal-fetal interface AUTHOR: Vikki M Abrahams, PhD SECTION EDITORS: Jordan S Orange, MD, PhD, CharlesJ Lockwood, MD, MHCM DEPUTY EDITOR: Elizabeth TePas, MD, MS All topics are updated as new evidence becomes available and our peer review process is complete Literature review current through: Apr 2024 This topic last updated: May 30, 2023 INTRODUCTION In pregnant females, local adaptation of the maternal immune system allows for successful coexistence between the mother and the semi-allograft that is the fetus/placenta expressing both maternal (self) and paternal (nonself) genes [1-4] Cytotoxic adaptive immune responses are diminished, bypassed, or even abrogated, while regulatory adaptive immunity is enhanced [5,6] By contrast, innate (natural) immunity remains intact, serving two purposes: one, to continue to provide host defense against infection, and two, to interact with fetal tissues to promote successful placentation and pregnancy [4,7-10] An introduction to the immunology of pregnancy and the maternal-fetal interface is presented in this topic review Basic immunologic concepts are reviewed separately (See "An overview of the innate immune system" and "The adaptive cellular immune response: T cells and cytokines”) IMMUNE DEFENSE MECHANISMS OF THE PLACENTA AND EXTRAPLACENTAL MEMBRANES The placenta and fetal membranes are directly exposed to maternal blood and tissues Thus, unique features of the cells that comprise this interface must underlie the remarkable ability of the genetically distinct fetal tissue to inhabit the maternal host Many immunologists studying reproduction agree that maternal immunity is not solely antagonistic to trophoblast tissue [11,12] Indeed, a maternal immune presence in the decidua https://www.uptodate.com/contents/immunology-of-the-maternal-fetal-interface/print?search=Immunology of the maternal-fetal interface&source=sea 1/32 5/15/24, 10:36 AM Immunology of the maternal-fetal interface - UpToDate is essential for successful implantation [4] Evidence of the opposite hypothesis (ie, that trophoblasts have offensive mechanisms for actively killing maternal lymphocytes) is lacking It is clear, however, that the placenta is normally protected from the killing functions of maternal cells through a number of immune-protective mechanisms [13] Trophoblast cells — Trophoblast cells are the specific placental cell layer that protects the embryo from those components of the maternal immune system dedicated to destroying foreign tissues The inner cell mass and resultant embryo are secluded and protected beneath a layer of trophoblastic cells throughout pregnancy (‘figure 1) Trophoblast cells are derived from the external trophectoderm layer of the blastocyst and develop into the placenta Precursor trophoblast cells choose one of three developmental pathways (see "Placental development and physiology" and "The placental pathology report"): ¢ They may remain quiescent in the villi as a pool of cells for future needs (villous cytotrophoblast cells) ¢ They may proliferate and migrate/invade into the decidua, ultimately forming the chorion membrane (extravillous cytotrophoblast cells) Extravillous trophoblast cells may also interact with maternal decidual immune cells and invade into the maternal spiral arteries, replacing the endothelial layer (endovascular trophoblast) ¢ They may merge into the developing syncytiotrophoblast through a process of cell fusion to create a multinucleate cell layer While this creates a barrier for the controlled movement and transport of molecules, the placenta is not an impermeable barrier There is evidence for the bidirectional movement of maternal and fetal cells [14] This may be explained, in part, by the presence of gaps in the syncytiotrophoblast, particularly later in gestation [15] These subpopulations of trophoblasts (extravillous cytotrophoblast cells, chorion membrane cytotrophoblasts, and endovascular trophoblasts) are variably exposed to maternal hematopoietic elements in the decidua, the fetal membranes, and in maternal blood either flowing over the fetal surface of the placenta (syncytiotrophoblasts) or within the spiral arteries (endovascular trophoblasts) Certain trophoblast cells (villous cytotrophoblast cells) are only rarely exposed to maternal blood Placental membranes — The placenta and its attached fetal membranes can protect themselves from maternal immune cell attack and modulate the local maternal immune system to promote and maintain normal placentation and pregnancy The mechanisms utilized vary with the state of differentiation and anatomic location of the trophoblast cells This cell type, https://www.uptodate.com/contents/immunology-of-the-maternal-fetal-interface/print?search=Immunology of the maternal-fetal interface&source=sea 2/32 5/15/24, 10:36 AM Immunology of the maternal-fetal interface - UpToDate which protects the embryo itself as well as certain components of the extraembryonic membranes that are derived from the inner cell mass, such as the amnion membrane, relies upon multiple strategies to avoid detection by potentially cytotoxic maternal immune cells and antibody-mediated cell destruction while influencing the local immune environment that is necessary for successful pregnancy [4] Specific immune-protective mechanisms Altered expression of HLA and related molecules — The primary cellular immune response that develops against transplanted tissue is directed against the major histocompatibility complex (MHC) proteins on donor tissue [16] In humans, the MHC proteins are called human leukocyte antigens (HLAs) The placenta is not a typical transplant, since proteins derived from HLA genes are not expressed codominantly on trophoblast cell membranes, unlike other cell types (See "Human leukocyte antigens (HLA): A roadmap" and "Transplantation immunobiology".) ¢ HLA class I - Strict regulation of the expression of specific HLA class I molecules in subpopulations of trophoblasts is believed to protect the fetus against maternal immune cells programmed to attack cells expressing foreign (paternal) HLA class I antigens The extravillous trophoblasts migrating into the decidua lack expression of HLA-A or HLA-B class Ia antigens that are primary stimulators of classical graft rejection and instead display a unique pattern of class Ia HLA-C and the nonclassical HLA class Ib molecules, HLA-E, HLA-F, and HLA-G [1,17,18] The genes encoding HLA-E, HLA-F, and HLA-G antigens have few alleles in comparison with HLA-A and HLA-B HLA-G, HLA-C, and HLA-F are expressed by first trimester extravillous trophoblast, and, as gestation proceeds, their expression weakens and becomes intracellular HLA-E is expressed by the extravillous trophoblast only in the first trimester [17] HLA-C, HLA-E, HLA-G, and HLA-F may act to dampen or modulate maternal immune responses by interacting with killer immunoglobulin-like receptors (KIRs) on decidual NK (dNK) cells, macrophages, and a subset ofT cells and with the T cell receptor on CD8+ T cells [1,18-21] The consequences of these interactions include activation of pathways in NK cells and macrophages that interfere with the killer functions of these cells [22,23] At the same time, HLA-E, HLA-F, and HLA-G may activate pathways in dNK cells, macrophages, and T cells that promote trophoblast migration and placentation [18,24,25] One mechanism by which HLA-G influences dNK cell and T cell function is through a process of trogocytosis, in which a lymphocyte transfers plasma membrane fragments containing cell surface molecules from an antigen-presenting cell to its own surface via the https://www.uptodate.com/contents/immunology-of-the-maternal-fetal-interface/print?search=Immunology of the maternal-fetal interface&source=sea 3/32 5/15/24, 10:36 AM Immunology of the maternal-fetal interface - UpToDate immunologic synapse [18] These acquired HLA-G* NK and T cells are immunosuppressive [26] The HLA class Ia antigen, HLA-C, is expressed on extravillous trophoblast and may have important interactions with leukocytes in some mothers [1,27] As an example, certain combinations of maternal KIRs and fetal HLA-C variants correlate with low birth weight and preeclampsia [28,29] HLA-C expression may be regulated by Nod-like receptor family pyrin domain-containing 2 (NLRP2) [30] HLA-G messenger ribonucleic acid (MRNA) can be alternatively spliced to yield membrane- bound and soluble variants Soluble HLA-G is associated with immunomodulatory functions and promotion of placentation [18,31] Antigen-presenting cells expressing either a soluble or membrane-bound form of HLA-G repress T cell alloproliferation via this pathway [32] Soluble HLA-G (HLA-G5) has been identified in maternal serum, is biochemically unique among the HLA-G isoforms, and is associated with specific immune modulation and the promotion of a pro-placentation environment [33-37] In contrast to migrating extravillous cells, syncytiotrophoblast forming the outermost layer of the placental villi that is exposed to maternal blood does not express membrane-bound HLA class I antigens [38] Syncytiotrophoblast in term placentas lacks HLA class IA mRNA (HLA-A, HLA-B, and HLA-C) and membrane-bound protein [1,18-20] However, there is evidence for HLA class IB (HLA-E, HLA-F, and HLA-G) mRNA and antigens in this continuous cell layer both early and late in pregnancy [1,18,34,39,40] ¢ HLA class II - The genes that encode potentially dangerous paternally derived foreign HLA class II HLA-D region molecules are entirely repressed in trophoblast cells None of the trophoblast subpopulations express HLA class II antigens either in vivo or in vitro Control over transcription of class II genes may be exerted by silencing of expression of the class II transactivator (CIITA), a transacting factor that is essential for constitutive and interferon (IFN) gamma-inducible MHC class II gene transcription [41] ¢ B7 family - Members of the B7 family of costimulatory molecules that have both lymphocyte stimulatory and inhibitory functions are expressed on trophoblast cells in human placentas and may play a critical role in maintaining tolerance to the fetus The B7H1 protein (programmed death ligand 1 [PD-L1]; CD274), which has lymphocyte inhibitory properties, is expressed on syncytiotrophoblast and, therefore, positioned to interfere with activation of lymphocytes circulating in maternal blood Interactions between villous and extravillous trophoblast PD-L1 (B7H1) and programmed cell death protein 1 (PD-1; CD279) expressed by maternal lymphocytes promote T regulatory (Treg) cell development and function and inhibit activated T cells (T helper cell type 17 [Th17] cells) [42-44] Another B7 family member, B7H3 has been reported to regulate trophoblast https://www.uptodate.com/contents/immunology-of-the-maternal-fetal-interface/print?search=Immunology of the maternal-fetal interface&source=sea 4/32 5/15/24, 10:36 AM Immunology of the maternal-fetal interface - UpToDate invasion through RhoA/Rho-dependent coiled-coil kinase (ROCK) 2 signaling and reduces dNK cell secretion of interleukin (IL) 8 and IFN-inducible protein (IP) 10 [45] ¢ IDO - Trophoblast cells produce indoleamine 2,3-dioxygenase (IDO), which depletes tryptophan by promoting its catabolism This is believed to inactivate T cells since they require tryptophan Although IDO is clearly important to survival of the mouse embryo, studies in IDO-/- knockout mice have failed to reveal any impact on pregnancy [46] Evidence is beginning to emerge in support of this potential mechanism in humans [47] One study reported that IDO* decidual macrophages supported trophoblast survival [48] ¢ TNF superfamily - Apoptosis-inducing members of the TNF supergene family may also have important roles in protecting the placenta and its membranes by inducing apoptosis in potentially cytotoxic T cells The ligands identified in and/or on human trophoblasts include TNF-alpha, FasL, and TRAIL, as well as a number of less well-characterized TNF superfamily members [49-52] Some of these latter ligands, which include B cell-activating factor (BAFF), may positively influence pregnancy host defenses by supporting maternal and/or fetal antibody production [53] All of these molecules, which are expressed as both membrane and soluble forms, can kill activated immune cells targeting the trophoblast by transducing an apoptotic signal via specific receptors on activated leukocytes FasL may be of particular importance since FasL prevents immune cell attack by interacting with leukocyte receptors (eg, Fas) in other organs such as the eye and the testis ¢ Microparticles - Placental-derived microparticles, such as microvesicles and exosomes that contain an array of placental proteins, MRNA, and microRNAs, are thought to play a role in regulating the maternal immune system during pregnancy Studies have shown that the trophoblast secretes active FasL via exosomes and microvesicles [54,55] Some B7 family members, as well as HLA-G and HLA-E, can also be released from the placenta via exosomes and microvesicles [56,57] The release and content of these microparticles are increased and/or altered under certain pathologic conditions, and, as such, they may be involved in the pathogenesis of pregnancy complications such as preeclampsia [58-61] Exosome-mediated transfer of placental-specific microRNAs regulates trophoblast and maternal cell immunity to viral infections [62] A novel mechanism by which maternal immune cells can signal to the placental unit via exosomes has been proposed [63] Soluble immunomodulators — Maternal immune modulation during pregnancy may also be conferred by the synthesis of immunosuppressive or immunoregulatory molecules As examples, the human placenta produces progesterone, prostaglandin Ez (PGE2), and https://www.uptodate.com/contents/immunology-of-the-maternal-fetal-interface/print?search=Immunology of the maternal-fetal interface&source=sea 5/32 5/15/24, 10:36 AM Immunology of the maternal-fetal interface - UpToDate antiinflammatory cytokines such as IL-10 and IL-4 [1,19,20,64,65] Progesterone may drive placental production of these antiinflammatory cytokines in placental cells just as it does in lymphocytes For example, IL-10 appears to stimulate production of HLA-G [66], and dysfunction of this pathway may be important in preeclampsia [67] Studies using IL-10-/- knockout mice have highlighted the potentially important protective role for this cytokine in pregnancy [68] Soluble thymic stromal lymphopoietin (TSLP) may also play a role TSLP secreted by trophoblast cells stimulates decidual dendritic cells (ADCs) to produce IL-10 and chemokine (C-C motif) ligand 17 (CCL17) [69] These activated dDCs induce T helper cell type 2 (Th2) differentiation of decidual T cells Lower levels of TSLP are seen in miscarriage than in normal pregnancy Complement proteins — Trophoblast cells express high levels of the following complement regulatory proteins: CD46 (membrane cofactor protein [MCP]), CD55 (decay accelerating factor [DAF]), and CD59 (membrane inhibitor of reactive lysis [MIRL]) [70,71] Complement regulatory proteins are critically important for protecting the extraembryonic tissues from maternal antipaternal cytotoxic antibodies since complement activation leads to opsonization and destruction of the immunologic target (the fetal cells) (See "Regulators and receptors of the complement system".) Mothers routinely produce high titers of antibodies to paternally derived HLA and unique trophoblast antigens, such as the unique placental isoform of alkaline phosphatase Antibody induction of complement-mediated lysis is prevented by high expression of CD46 and DAF in various subpopulations of trophoblast cells Evidence supporting a role for complement proteins in placental immune protection is provided by genetic deletion experiments In mice, the absence of the complement regulatory protein derived from Crry gene leads to placental disruption due to complement deposition in the placenta and lysis of cells at the implantation site, followed by a massive inflammatory reaction and fetal demise [72] LOCAL IMMUNE ADAPTATION IN THE PREGNANT UTERUS Dramatic changes take place in the uterus during pregnancy that also help contribute to immune acceptance of and/or crosstalk with the fetus/placenta to promote a successful pregnancy Differences in lymphocyte populations — The first histologically apparent maternal immunologic adjustment to the embryo is a dramatic change in the relative proportions of https://www.uptodate.com/contents/immunology-of-the-maternal-fetal-interface/print?search=Immunology of the maternal-fetal interface&source=sea 6/32 5/15/24, 10:36 AM Immunology of the maternal-fetal interface - UpToDate leukocyte subpopulations in the uterus The endometrial natural killer (NK) cell population shifts from uterine NK (UNK) cells to decidual NK (dNK) cells (CD56°"9"tcD16>), and this phenotype is distinct from both CD56"9"t and CD56%'™ peripheral blood NK (pNkK) cells [73] The origin of dNK cells remains controversial as it is unclear whether these cells are recruited from the periphery, if the local environment drives their unique phenotype, or both Furthermore, their function is thought to be distinct given that many genes, including some with immunomodulatory properties, are overexpressed in dNK cells when compared with their peripheral counterparts [73] Invading fetal trophoblasts become admixed with dNK cells, macrophages, and dendritic cells that account for approximately 70, 20, and 2 percent, respectively, of all cells in the decidua [74-76] In addition, the uterine T cell population during pregnancy expands across gestation and is mostly regulatory in nature [77] Decidual macrophages exhibit phenotypic elasticity, adapting to the local microenvironment During the peri-implantation period, decidual macrophages display an M1 (inflammatory) phenotype During the period of placentation, there is a mixture of M1 (inflammatory) and M2 (antiinflammatory) decidual macrophages, which shift to predominantly M2 after placentation [78,79] The placenta may promote this via secreted factors [80] At parturition, there is an accumulation of M1 decidual macrophages [78,79] There are also subsets outside of conventional phenotyping [78,81] While decidual macrophages may help to prevent uterine infections in pregnant females, some studies suggest that trophoblast-macrophage crosstalk is more important for promoting normal placentation by being involved in implantation, placental development, immunoregulation, vascular remodeling, and tissue homeostasis [9,80,82-84] Aberrant macrophage numbers and activation may play a role in pregnancy complications, such as preeclampsia, intrauterine growth restriction (IUGR), or preterm birth [9,85,86] Macrophages are also present throughout gestation in the placental villi and are known as Hofbauer cells These fetally derived immune cells also display a M2 phenotype, although they can generate strong inflammatory responses to infectious triggers Hofbauer cell numbers are also altered in pregnancy complications such as preeclampsia and chorioamnionitis [87-89] Similarly, the major roles of dNK cells may also be unique to pregnancy [90] Although dNK cells express a high level of cytotoxic factors, they are unable to form cytotoxic synapses to deliver granule contents to trophoblast cells [91] and instead appear to play a role in trophoblast attraction and invasion, decidual and placental angiogenesis and possibly fetal vasculogenesis, and vascular modifications in the uterus [92-95] However, dNK cells are able to kill virally infected trophoblast cells, indicating a mechanism to protect the fetus [96] A population of UNK cells that are found in repeated pregnancies has been identified These "memory-like" UNK cells may be involved in promoting placentation [97] One study proposed that UNK cells maintain endometrial homeostasis by clearing senescent decidual cells [98] As with macrophages, https://www.uptodate.com/contents/immunology-of-the-maternal-fetal-interface/print?search=Immunology of the maternal-fetal interface&source=sea 7/32 5/15/24, 10:36 AM Immunology of the maternal-fetal interface - UpToDate alterations in dNK cell numbers and activation status may play a role in pregnancy complications, such as immunologic infertility, recurrent spontaneous abortion, and preeclampsia [28,29,99-103] Excessive dNK cell recruitment and/or expansion, as well as elevated cytotoxic activity, have been associated with pregnancy disorders such as implantation failure and miscarriage [102] However, some studies suggest the opposite that deficiencies in UNK numbers are associated with recurrent pregnancy loss, highlighting the need to reassess approaches to NK cell profiling in patients with adverse outcomes [104,105] NK cell depletion compromises pregnancy in mice, further underscoring their importance during pregnancy [106] Innate lymphoid cells (ILCs) distinct from NK cells have been characterized in the human fully decidua During early pregnancy, group 3 ILCs (ILC3) are found While their function is not levels understood, ILC3s may establish functional interactions with stromal cells, regulate the recruitment and function of other maternal immune cells, and contribute to vascular remodeling [107,108] At term, both ILC2s and ILC3s have been found in the decidua, and may increase in preterm birth [109] The role of decidual dendritic cells (dDCs) is less clear, although mouse studies have demonstrated that these cells are critical for successful implantation and may also be involved in remodeling of the maternal vasculature [6,110,111] However, alternative views exist One is that dendritic cells may promote systemic immune tolerance during pregnancy [112] Another is that dendritic cells are trapped in the decidua to prevent the exposure of peripheral T cells to fetal antigens [113] Uterine dendritic cells are also thought to contribute to pregnancy success by influencing NK cell function and the cytokine profile at the maternal-fetal interface [114] Depletion of uterine dendritic cells in mice results in a severe impairment of implantation and embryo resorptions, highlighting their importance [111] Preeclampsia is also associated with persistence of decidual basalis macrophages and recruitment of dendritic cells [115,116] One hindrance of our understanding of the presence and function of dendritic cells at the maternal- fetal interface is that there are many subpopulations, and there is a lack of comprehensive phenotyping However, new immunophenotyping approaches are emerging [11 7] Gamma-delta T cells and a population of double-negative T lymphocytes (CD47/CD8>) have been reported in pregnant uteri [118,119] Their roles are unclear, although immunosuppressive gammaz-delta T cells may play a role in regulating the maternal immune system to protect the maternal-fetal interface from aggressive immune responses [120,121] Increased numbers of gamma-delta T cells may be associated with pregnancy loss [121] It was once thought that CD8* effector T cells in normal pregnancy were eliminated from or prevented from entering the maternal-fetal interface However, studies have suggested that there is a population of highly https://www.uptodate.com/contents/immunology-of-the-maternal-fetal-interface/print?search=Immunology of the maternal-fetal interface&source=sea 8/32 5/15/24, 10:36 AM Immunology of the maternal-fetal interface - UpToDate differentiated CD8* effector memory T cells within the pregnant decidua The antigenic target of these cells is still unclear, as is their function and whether they are protective [122-124] CD4*CD25* regulatory T cells (Tregs) are also present in the decidua of normal pregnant females, and their presence and expansion during pregnancy are thought to be triggered in both alloantigen-dependent and alloantigen-independent manners [5,125,126] In human cocultures of HLA-G* extravillous trophoblast cells and CD4* T cells, there is an increase in the number of cells expressing a Treg phenotype [127] These fetal-specific Tregs persist after delivery and rapidly reaccumulate during subsequent pregnancies, indicating a memory response [128] In a mouse model, increased numbers of Tregs are seen in response to an antigenic fetus [129] Selective killing of these Tregs results in fewer antigenic offspring There are decreased numbers of peripheral blood and decidual Treg cells in females with preeclampsia compared with normal pregnancy subjects These findings suggest that Tregs play a role in maternal tolerance to the fetus [126,130,131] A subpopulation of CD4* interleukin (IL) 17-producing T cells (T helper cell type 17 [Th17]) have also been described in pregnancy Their numbers are also expanded in the pregnant uterus, although not as much as CD4*CD25* Tregs While they are inflammatory in nature, the presence of Th17 cells may play a role in protecting the maternal-fetal interface from microbes, and the Tregs present may serve to regulate their function Thus, altered numbers of Th17 and/or ratio of Th17 to Tregs are associated with pregnancy complications, such a spontaneous abortion, preeclampsia, and preterm birth [126,132] Mast cells are classically associated with allergic immune responses However, in pregnancy, their presence in the decidua may contribute to successful placentation Uterine mast cells expand in early pregnancy in the mouse [133] and are higher in human pregnancies compared with nonpregnant females [134] In the mouse, they have been shown to promote an antiinflammatory state and contribute to tissue remodeling, angiogenesis, and spiral artery transformation [133] In mice, glycan-mediated B cell suppression in pregnancy may prevent B cell responses to placental antigens [135] At the same time, a subset of IL-10-producing regulatory B cells (CD19*CD5*CD1d*) has been shown to expand peripherally in mice and humans during pregnancy In abortion-prone mice, expansion of these regulatory B10 cells is not seen, and fetal rejection can be prevented by adoptive transfer of these cells from normal pregnant mice [136,137] While the presence of CD19" B cells in the human decidua throughout pregnancy has been reported [138,139], the importance of regulatory B cells in the human decidua remains to be determined https://www.uptodate.com/contents/immunology-of-the-maternal-fetal-interface/print?search=Immunology of the maternal-fetal interface&source=sea 9/32 5/15/24, 10:36 AM Immunology of the maternal-fetal interface - UpToDate Soluble immunomodulatory agents — Uterine immune regulation is also provided by the induction of immunomodulatory molecules that permeate the uterine environment These principally include progesterone, prostaglandins, and some cytokines Progesterone — Progesterone, the dominant hormone of pregnancy, is initially produced by the corpus luteum Subsequently, the placenta is responsible for almost all progesterone synthesis High concentrations of progesterone can suppress the maternal immune response [140] As an example, progesterone alters the T helper cell type 1 (Th1)/T helper cell type 2 (Th2) balance and inhibits production of tumor necrosis factor (TNF) alpha in both mouse and human macrophages [141,142] Prostaglandin E2 — Prostaglandin Ez (PGE2) is produced by resident macrophages and decidual cells Lymphocytes proliferate poorly in the presence of this compound Cytokines — High levels of Th2-type cytokines are typical of mouse pregnancy [143,144] but are less definitive in pregnant females Nonetheless, many still consider human pregnancy to be a Th2 antiinflammatory condition and that a shift towards Th1 cytokines will lead to abortion or pregnancy complications As an example, elevated levels of IL-6 in cervicovaginal and amniotic fluid, but not plasma, was associated with spontaneous preterm birth [145] Similarly high levels of proinflammatory IL-1-beta and TNF-alpha in the amniotic fluids are associated with preterm birth [146,147] While disruption in cytokine profiles during pregnancy may be detrimental, it is important to appreciate that human pregnancy is both proinflammatory and antiinflammatory, depending upon the stage of gestation, rather than focusing on the murine Th1/Th2 terminology [4,125,148] What is clear is that the appropriate balance of cytokine and chemokine expression at the maternal-fetal interface can govern the immune cell profile and function within the decidua For example, one study demonstrated in mice that effector T cells cannot accumulate within the decidua, in part because of the epigenetic silencing of key chemokine genes in decidual stromal cells [149] In contrast, the expression of specific cytokines and chemokines by the decidua and placenta are critical for recruitment and maintenance of pro-pregnancy immune cells [150] MATERNAL SYSTEMIC IMMUNE RESPONSES The pregnant immune system bears markers of both immune activation and dampening However, the consensus is that there is no generalized immunosuppression of maternal immune responses in pregnancy However, selective suppression or modulation may occur https://www.uptodate.com/contents/immunology-of-the-maternal-fetal-interface/print?search=Immunology of the maternal-fetal interface&source=se 10/32 5/15/24, 10:36 AM Immunology of the maternal-fetal interface - UpToDate 28 Hiby SE, Walker JJ, O'shaughnessy KM, et al Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success.J Exp Med 2004; 200:957 29 Moffett A, Colucci F Co-evolution of NK receptors and HLA ligands in humans is driven by reproduction Immunol Rev 2015; 267:283 30 Tilburgs T, Meissner TB, Ferreira LMR, et al NLRP2 is a suppressor of NF-kB signaling and HLA-C expression in human trophoblasts†,‡ Biol Reprod 2017; 96:831 31 Fournel S, Aguerre-Girr M, Huc X, et al Cutting edge: soluble HLA-G1 triggers CD95/CD95 ligand-mediated apoptosis in activated CD8+ cells by interacting with CD8.J Immunol 2000; 164:6100 32 Naji A, Durrbach A, Carosella ED, Rouas-Freiss N Soluble HLA-G and HLA-G1 expressing antigen-presenting cells inhibit T-cell alloproliferation through ILT-2/ILT-4/FasL-mediated pathways Hum Immunol 2007; 68:233 33 HuJSn , Jt adhav L, Chu W, et al Soluble HLA-G circulates in maternal blood during pregnancy Am J Obstet Gynecol 2000; 183:682 34 Morales PJ, Pace JL, Platt JS, et al Synthesis of beta(2)-microglobulin-free, disulphide-linked HLA-G5 homodimers in human placental villous cytotrophoblast cells Immunology 2007; 122:179 35 Kdstlin N, Ostermeir AL, Spring B, et al HLA-G promotes myeloid-derived suppressor cell accumulation and suppressive activity during human pregnancy through engagement of the receptor ILT4 EurJ Immunol 2017; 47:374 36 Lee CL, Guo Y, So KH, et al Soluble human leukocyte antigen G5 polarizes differentiation of macrophages toward a decidual macrophage-like phenotype Hum Reprod 2015; 30:2263 37 van der Meer A, Lukassen HG, van Cranenbroek B, et al Soluble HLA-G promotes Th1-type cytokine production by cytokine-activated uterine and peripheral natural killer cells Mol Hum Reprod 2007; 13:123 38 Hunt JS, FishbacJkL, Andrews GK, Wood GW Expression of class I HLA genes by trophoblast cells Analysis by in situ hybridization.J Immunol 1988; 140:1293 39 Hunt JS, Fishback JL, Chumbley G, Loke YW Identification of class IMHC mRNA in human first trimester trophoblast cells by in situ hybridization.J Immunol 1990; 144:4420 40 Chu W, Fant ME, Geraghty DE, Hunt JS Soluble HLA-G in human placentas: synthesis in trophoblasts and interferon-gamma-activated macrophages but not placental fibroblasts Hum Immunol 1998; 59:435 https://www.uptodate.com/contents/immunology-of-the-maternal-fetal-interface/print?search=Immunology of the maternal-fetal interface&source=se 18/32 5/15/24, 10:36 AM Immunology of the maternal-fetal interface - UpToDate 41 Murphy SP, Tomasi TB Absence of MHC class II antigen expression in trophoblast cells results from a lack of class II transactivator (CIITA) gene expression Mol Reprod Dev 1998; 51:1 42 Petroff MG, Chen L, Phillips TA, et al B7 family molecules are favorably positioned at the human maternal-fetal interface Biol Reprod 2003; 68:1496 43 Petroff MG, Perchellet A B7 family molecules as regulators of the maternal immune system in pregnancy Am J Reprod Immunol 2010; 63:506 44 Linscheid C, Petroff MG Minor histocompatibility antigens and the maternal immune response to the fetus during pregnancy Am J Reprod Immunol 2013; 69:304 45 Zhang D, Yu Y, Ding C, et al Decreased B7-H3 promotes unexplained recurrent miscarriage via RhoA/ROCK2 signaling pathway and regulates the secretion of decidual NK cellstT Biol Reprod 2023; 108:504 46 Munn DH, Zhou M, Attwood JT, et al Prevention of allogeneic fetal rejection by tryptophan catabolism Science 1998; 281:1191 47 Ban Y, Zhao Y, Liu F, et al Effect of Indoleamine 2,3-Dioxygenase Expressed in HTR-8/SVneo Cells on Decidual NK Cell Cytotoxicity Am J Reprod Immunol 2016; 75:519 48 Huang HL, Yang HL, Lai ZZ, et al Decidual IDO+ macrophage promotes the proliferation and restricts the apoptosis of trophoblasts J Reprod Immunol 2021; 148:103364 49 Hunt JS, Chen HL, Miller L Tumor necrosis factors: pivotal components of pregnancy? Biol Reprod 1996; 54:554 50 Runic R, Lockwood CJ, Ma Y, et al Expression of Fas ligand by human cytotrophoblasts: implications in placentation and fetal survival.J Clin Endocrinol Metab 1996; 81:3119 51 Phillips TA, Ni J, Pan G, et al TRAIL (Apo-2L) and TRAIL receptors in human placentas: implications for immune privilege.J Immunol 1999; 162:6053 52 Phillips TA, NiJ, Hunt JS Death-inducing tumour necrosis factor (TNF) superfamily ligands and receptors are transcribed in human placentae, cytotrophoblasts, placental macrophages and placental cell lines Placenta 2001; 22:663 53 Phillips TA, NiJ, Hunt JS Cell-specific expression of B lymphocyte (APRIL, BLyS)- and Th2 (CD30L/CD153)-promoting tumor necrosis factor superfamily ligands in human placentas.J Leukoc Biol 2003; 74:81 54 Abrahams VM, Straszewski-Chavez SL, Guller S, Mor G First trimester trophoblast cells secrete Fas ligand which induces immune cell apoptosis Mol Hum Reprod 2004; 10:55 55 Frangsmyr L, Baranov V, Nagaeva O, et al Cytoplasmic microvesicular form of Fas ligand in human early placenta: switching the tissue immune privilege hypothesis from cellular to https://www.uptodate.com/contents/immunology-of-the-maternal-fetal-interface/print?search=Immunology of the maternal-fetal interface&source=se 19/32 5/15/24, 10:36 AM Hum Reprod Immunology of the maternal-fetal interface - UpToDate vesicular level Mol 2005; 11:35 56 Kshirsagar SK, Alam SM, Jasti S, et al Imnmunomodulatory molecules are released from the first trimester and term placenta via exosomes Placenta 2012; 33:982 57 Jiang L, Fei H, Jin X, et al Extracellular Vesicle-Mediated Secretion of HLA-E by Trophoblasts Maintains Pregnancy by Regulating the Metabolism of Decidual NK Cells IntJ Biol Sci 2021; 17:4377 58 Mincheva-Nilsson L, Baranov V The role of placental exosomes in reproduction AmJ Reprod Immunol 2010; 63:520 59 Redman CW, Sargent IL Circulating microparticles in normal pregnancy and pre-eclampsia Placenta 2008; 29 Suppl A:S73 60 Holder BS, Tower CL, Forbes K, et al Immune cell activation by trophoblast-derived microvesicles is mediated by syncytin 1 Immunology 2012; 136:184 61 Li H, Ouyang Y, Sadovsky E, et al Unique microRNA Signals in Plasma Exosomes from Pregnancies Complicated by Preeclampsia Hypertension 2020; 75:762 62 Delorme-Axford E, Donker RB, MouilleJtF, et al Human placental trophoblasts confer viral resistance to recipient cells Proc Natl Acad Sci U S A 2013; 110:12048 63 Holder B, Jones T, Sancho Shimizu V, et al Macrophage Exosomes Induce Placental Inflammatory Cytokines: A Novel Mode of Maternal-Placental Messaging Traffic 2016; 17:168 64 Denison FC, Kelly RW, Calder AA, Riley SC Cytokine secretion by human fetal membranes, decidua and placenta at term Hum Reprod 1998; 13:3560 65 Hunt JS Cytokine networks in the human placenta In: Cytokines in human reproduction, Hi Il JA (Ed), Wiley-Liss, New York 1999 p.203 66 Moreau P, Adrian-Cabestre F, Menier C, et al IL-10 selectively induces HLA-G expression in human trophoblasts and monocytes Int Immunol 1999; 11:803 67 Hennessy A, Pilmore HL, Simmons LA, Painter DM A deficiency of placental IL-10 in preeclampsia.J Immunol 1999; 163:3491 68 Thaxton JE, Sharma S Interleukin-10: a multi-faceted agent of pregnancy Am J Reprod Immunol 2010; 63:482 69 Guo PF, Du MR, Wu Hx, et al Thymic stromal lymphopoietin from trophoblasts induces dendritic cell-mediated regulatory TH2 bias in the decidua during early gestation in humans Blood 2010; 116:2061 70 Hsi BL, Hunt JS, Atkinson JP Differential expression of complement regulatory proteins on subpopulations of human trophoblast cells J Reprod Immunol 1991; 19:209 https://www.uptodate.com/contents/immunology-of-the-maternal-fetal-interface/print?search=Immunology of the maternal-fetal interface&source=se 20/32