Abstract
Purpose of Review
Because the fetus expresses paternally-derived foreign antigens, pregnancy poses unique immune challenges. The maternal immune system must balance protecting the semi-allogeneic fetus from immune rejection with defending the mother and fetus from pathogens. Fetally-derived trophoblast cells of the placenta serve as the immunologic interface with soluble and cellular maternal immune effectors and are thereby essential partners in supporting these tightly regulated interactions. While there are multiple ways that the maternal–fetal immune interface is controlled in a healthy pregnancy, this review highlights several of the immune checkpoint regulators thought to be centrally involved in maternal–fetal immunoregulation.
Recent Findings
Reproductive immunologists have shown that those fetal trophoblast cells that directly encounter maternal immune cells share many common features with cancer cells, shifting the paradigm of placental immunology away from transplantation biology and toward our extensive understanding of tumorigenesis. Both the post-implantation placenta and the growing neoplasm have many shared goals, including invasion, robust cellular proliferation, angiogenesis, and modulation of host immunity. One way in which both the human placenta and cancer cells protect themselves from immune attack is through the loss of, or neoexpression of, several important cell surface regulators of specific immune interactions known as immune checkpoints. Here, we will discuss several ways that tumors and the placenta utilize immune checkpoint pathways and inhibitors, including the loss of most classical major histocompatibility complex (MHC) molecules and neoexpression of several nonclassical MHC molecules, expression of novel immunosuppressive B7 family members and cell adhesion molecules, such as CD47, and modulation of indoleamine 2,3-dioxygenase (IDO) enzyme activity.
Summary
Finely tuned immune adaptation is fundamental to a successful reproduction. Failure to implement such adaptations can result in a variety of disorders, including pregnancy loss, abnormal placental invasion (e.g., placenta accreta/percreta), preeclampsia, and intrauterine growth restriction. Improved understanding of complex maternal-fetal immune interactions will be crucial to discover mechanisms underpinning these pregnancy complications, which, in turn, will help inform preventative and/or therapeutic clinical interventions.
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Introduction
A successful pregnancy requires tight regulatory control of the maternal immune system. Tasked with tolerance of the semi-allogeneic fetus, the maternal immune system must simultaneously retain the ability to respond to harmful pathogens while allowing for the placental growth and invasion [1]. This balance is especially important in early pregnancy during the placentation process, a series of events with remarkable similarity to tumorigenesis. Both the developing placenta and the invading tumor require robust cell proliferation, establishment of a vasculature via angiogenesis, and, most pertinent to this discussion, invasion of host tissues and modulation of host immune responses. These processes are all tightly linked. Invasion of the maternal decidua basalis by extravillous cytotrophoblasts (EVTs) allows for the remodeling of the uterine spiral arteries to optimize nutrient and oxygen exchange between the mother and her developing fetus [2]. Alterations in this invasion process have been proposed to be etiologic in several pregnancy derangements, including recurrent pregnancy loss, preeclampsia, fetal growth restriction, and preterm labor [3].
Immune checkpoints include enzymatic pathways and cell surface molecules that regulate immune interactions. They have been shown to be central in balancing immune responses in a way that enables robust response to exogenous insults without risking over-response to native antigens or to pregnancy [4, 5]. In this review, we describe the regulation, often inhibitory, of several immune checkpoint mechanisms that are thought to be important to pregnancy maintenance and normal fetal development and make comparisons to their similar role in neoplastic growth.
MHC Molecules
The major histocompatibility complex (MHC), also known in humans as the human leukocyte antigen (HLA) complex, is the most polymorphous set of genes in the human genome [6]. The HLA genes code for surface glycoproteins that function through the presentation of both endogenous and foreign antigens to the host immune system, largely to distinguish between self and non-self or altered-self (e.g., pathogen or neoplasm) antigens [7].
There are 3 main classes of HLA molecules: HLA class I, HLA class II, and HLA class III [8]. HLA class I is expressed on the surface of almost every somatic cell, with differing levels of expression based on tissue type. Playing an essential role in defending against intracellular pathogens, there is further division of MHC class I molecules into Class IA (classical) and Class IB (non-classical). The classical HLA molecules include HLA-A, HLA-B, and HLA-C. These gene products present antigens to cytotoxic CD8 + T cells, and their presence or absence regulates the function of natural killer (NK) cells and natural killer T (NKT) cells. The nonclassical HLA gene products include HLA-E, HLA-F, and HLA-G. These glycoproteins have a more limited variation in the antigens that they can present to leukocytes due to limited gene polymorphism [3, 6]. Their role in true antigen presentation is much more limited than that of HLA-A and -B, and their expression is limited to a much smaller group of cell types.
Important and characteristic MHC molecule expression patterns are essential to immune interactions at the developing maternal fetal interface [9]. Many trophoblast cells in the human placenta have very low to no expression of the classical HLA-A and -B molecules, and no trophoblast cell expresses MHC class II molecules [10]. This loss of expression is also seen in many tumors [11] and is a good example of the loss of a major cell surface immune molecules that may be considered immune checkpoints. In contrast, the classical MHC molecule, HLA-C, and the non-classical MHC products, HLA-E, HLA-G, and possibly HLA-F, are expressed on the surface of the most invasive of the trophoblast cell types, the EVTs [3]. This fairly unusual overall pattern of MHC expression is not uncommon in tumor cell types [12], and the expression of HLA-G, -E, and, to a lesser extent, -F, is quite limited to the placenta and to tumor cells.
HLA-G
HLA-G has seven different transcript isoforms, some coding for membrane-bound proteins (HLA-G1, G2, G3, and G4) and others for soluble proteins (G5, G6, G7; also known as sHLA-G). HLA-G is a ligand for three main receptors: immunoglobulin-like transcript 2/leukocyte immunoglobulin–like receptor subfamily B member 1/CD85 antigen-like family member J (ILT2 /LILRB1/ CD85j) found on T cells, NK cells, and B cells; immunoglobulin-like transcript 4/leukocyte immunoglobulin–like receptor subfamily B member 1/CD85 antigen-like family member B (ILT4/LILRB2/ CD85d) found on myeloid cells; and killer cell immunoglobulin-like receptor 2DL4 (KIR2DL4/CD158d) found on NK cells [13,14,15,16]. The KIR2DL4 receptor is a type of killer cell immunoglobulin–like receptor (KIR) that has both stimulatory and inhibitory functions. Residing primarily within endosomes, this receptor interacts with sHLA-G released by trophoblast cells, downregulating the cytotoxicity of decidual NK cells while stimulating the release of proinflammatory and pro-angiogenic cytokines, including interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), interferon-γ (IFN-γ), and tumor necrosis factor α (TNF-α) [17,18,19]. This proinflammatory response is essential for the promotion of decidual remodeling by invading EVTs. ILT2 and ILT4 are the primary inhibitory receptors for HLA-G. ILT2, in particular, plays a major role in suppressing NK and CD8 + T cell cytotoxicity and induces a more tolerogenic phenotype among dendritic cells and macrophages [20]. These receptors also promote IFN-γ release which, in turn, drives spiral artery remodeling within the basalis decidua [10].
Studies have shown that, in addition to direct inhibition of NK and CD8 + T cell cytotoxic activities, the presence of HLA-G on fetal trophoblast cells indirectly protects them from immune destruction through the actions of regulatory T cells (Tregs). Tregs maintain the pro-inflammatory/anti-inflammatory equilibrium in immune responses. At the maternal fetal interface, these cells are activated by fetal antigens presented by MHC class II molecules [3]. It is hypothesized that the Treg response to pregnancy is largely dependent on the recognition that fetal tissue is allogeneic. To this point, when fetal/maternal HLA mismatching increases, so too does the production and conversion of T cells into Tregs in order to inhibit an alloreactive T cell response [21]. HLA-G has been specifically shown to induce differentiation of CD4 + T cells into Tregs [22]. Clinically, abnormalities in HLA-G expression and activities have been implicated in several pregnancy-related disease processes, including recurrent pregnancy loss and preeclampsia [3].
HLA-F
HLA-F is a Class Ib HLA molecule that can be found on EVT cells. The two main receptors for this ligand are killer cell immunoglobulin–like receptor 3DL1 (KIR3DL1) and killer cell immunoglobulin–like receptor, three Ig domains and long cytoplasmic tail 2 (KIR3DL2), which are both inhibitory receptors expressed on decidual NK cells [5]. HLA-F binds longer peptides for antigen presentation than other MHC class I molecules. In its open conformation form, antigenic peptide and the typical binding partner for MHC class I molecules, beta 2-microglobulin, are absent. This open conformation allows for interactions between HLA-F heavy chains and other HLA molecules, including HLA-E. Such interactions are believed to help to stabilize ligand-receptor pairing between decidual NK cells and EVTs [16, 23], relegating HLA-F to a largely “assistant” role for other placental MHC I interactions.
HLA-E
HLA-E is an MHC class IB protein expressed both in the cytoplasm and on the surface of EVTs [24]. The main receptors for HLA-E are natural killer cell receptor 2C (NKG2C) on decidual NK cells, natural killer cell receptor 2A (NKG2A) on decidual NK cells, and CD8 + on T cells. Cell surface expression of HLA-E helps to protect cells from cytotoxic damage by presenting peptides derived from other HLA class I molecules to NK and CD8 + T cells. In particular, it protects HLA-G-containing cells through the presentation of HLA-G signal peptides to inhibitory receptors on otherwise cytotoxic immune cells, allowing HLA-G to indirectly promote immune tolerance through HLA-E [16].
HLA-C
As the only HLA Class IA protein expressed by fetal EVTs, maternally derived HLA-C plays an important role in alerting the maternal immune system to potential pathogens through typical antigen presentation to maternal CD8 + T cells. However, the polymorphic nature of HLA-C often leads to dissimilarity between the trophoblast-expressed paternally derived HLA-C alleles and the maternal HLA-C phenotype. This allele mismatch has the potential to increase cytotoxic/cytolytic activation of decidual T cells and NK cells toward fetal tissue [25]. Although studies have been mixed regarding the exact role of HLA-C mismatch in pregnancy complications, evidence of HLA-C specific antibodies in patients with recurrent miscarriage highlights the potential role that HLA-C allele mismatch may play in unexplained recurrent pregnancy loss [26, 27].
B7 Immune Checkpoint Molecules
The B7 family of molecules, a group of immune checkpoint proteins, is one of the best-characterized and widely-distributed signaling molecule superfamilies; their primary role is to serve as signaling mechanisms that modulate T cell activation [28,29,30]. The 11 known members of the B7 family are B7-1 (CD80), B7-2 (CD86), B7-H1 (programmed cell death ligand 1, PD-L1, CD274), B7-DC (PD-L2, CD273, PDCD1LG2), B7-H2 (ICOS-L), B7-H3, B7-H4 (VTCN1), B7-H5 (VISTA), BTNL2 (butyrophilin-like 2, BTL-II), B7-H6, and B7-H7 (HHLA2). Members of this superfamily can exert both stimulatory and inhibitory signals that depend on the cell type- and location-specific B7 family member ligand pairing [31].
B7 and Human Trophoblast
B7-H1, B7-H2, B7-DC, B7-H3, and B7-H4 are expressed in the human placenta, and their levels fluctuate during different stages of pregnancy [32, 33]. B7-H1 is highly expressed in the syncytiotrophoblast (STB) in early and term normal human placenta [32], while B7-DC and B7-H4 are prominent on the surface of STB during early pregnancy but are not present in human trophoblast at term [33]. B7-DC is abundant in first trimester STB, but absent in term STB, when localization has largely switched to placental endothelial cells [33]. B7-DC exhibits a higher affinity for programmed cell death protein 1 (PD-1; see below) than B7-H1, but its expression in the placenta is, comparatively, much more limited. Still, its interactions with PD-1 profoundly inhibit B7-CD28 signals at relatively low antigen concentrations and can thereby play an important role in promoting T cell proliferation and inflammatory cytokine production in the placenta [34, 35]. B7-H4 is expressed at high levels on early gestation STB [36], as well as on decidual macrophages [37]. B7-H4 plays an important role in early placental development by inhibiting the expression of classical MHC Class I molecules, shifting the differentiation of cytotrophoblast cells from invasion to syncytialization and inducing changes in peripheral natural killer cells that make them more closely mimic a decidual NK cell phenotype [38].
B7-H2 is expressed on EVT cells, macrophages, and Tregs in the first trimester and term placenta [33]. B7-H2 expression is associated with largely protolerogenic T helper 2 (Th2) cell effector function in terms of cell surface marker expression, differentiation, and cytokine production [39,40,41]. Similar to B7-H2, B7-H3 is narrowly expressed on the surface of EVTs and macrophages in the first trimester and term placenta [33]. Here, it is considered a coinhibitory molecule for T cells [42, 43]. In addition to its role in immunological pathways, B7-H3 has nonimmunologic, protumorigenic activities, including the promotion of cell migration and invasion, inhibition of apoptosis, and enhancement of cell viability, chemoresistance, and endothelial-to-mesenchymal (EMT) transition [44]. B7-H5, also known as VISTA, is well known for immune checkpoint inhibition, regulating host T cell and myeloid functions in the tumor microenvironment [45,46,47]. However, high B7-H5 expression levels have also been detected in trophoblast cells, including STB, EVT, and CTB (cytotrophoblast cells) from term human placentas [48, 49]. Its role in placental function and dysfunction remains to be determined.
B7 and Decidual Immune Cells
The expression of B7-1 and B7-2 is largely restricted to lymphoid cells, mainly class II human leukocyte antigen (HLA) + cells, including decidual dendritic cells (DCs) and macrophages at the maternal–fetal interface [28]. B7-1 and B7-2 assist decidual DCs in maintaining a largely protolerogenic, Th2-dominant state that is thought to be beneficial to gestational outcomes. Engagement of B7-1 or B7-2 with its ligand, cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), leads to the production of indoleamine 2,3-dioxygenase (IDO), an enzyme that is highly expressed at the human maternal–fetal interface and is capable of influencing T cell-related fetal rejection (see below) [50, 51]. Levels of B7-1 and B7-2 expression are higher in decidual macrophages isolated from early/mid-pregnancy than from those isolated at term [52], suggesting their involvement in human placental development and implantation.
The increased surface expression of B7-H1 on healthy, human decidual CD4 + T cell, Treg, NKT-like, and CD56 + NK cell subsets is accompanied by an increase in expression of the PD-1 immune checkpoint molecule in decidual immune cells. This strongly suggests that B7-H1/PD-1 interactions maintain a protolerogenic local immunological environment at the maternal–fetal interface by interacting with a variety of decidual immune cells.
Human BTNL2 has been identified as a B7-like molecule within the butyrophilin (BTN) gene family that is encoded by the MHC locus in humans [53]. BTNL2 may play an important role in inflammation and immune response by controlling T cell responses and promoting the generation of Tregs [54, 55]. Recombinant BTNL-2-Ig is now being studied as a potential treatment for graft-versus-host disease [56], suggesting it could also serve as a modulator of maternal–fetal immune interactions, either endogenously or as an exogenous therapy. To date there are no published reports on BTNL2 in the human placenta.
B7 Family Tumor Markers
Currently, there is not data to support the expression of the well-known tumor markers, B7-H6 and B7-H7, in pregnancy-related tissues [57, 58]. Their roles in tumorigenesis, however, suggest they could exert immunomodulatory activities that could support placental development. B7-H6 is selectively expressed by tumor cells, and its downregulation makes tumor cells vulnerable to NK-mediated tumor lysis [58]. B7-H7 (H long terminal repeat-associating 2, HHLA2) is expressed on monocytes and stimulated B cells and inhibits cytokine production by, and proliferation of, CD4 + and CD8 + T cells [59].
Soluble and Exosomal B7 Molecules
In addition to their cellular expression in trophoblast cell subtypes and decidual immune cells, alterations have been observed in the soluble forms of certain B7 molecules, such as B7-H1 and B7-H4, in pregnant women. Soluble B7-H1 levels were reported to be higher in the sera of pregnant women than in non-pregnant and postpartum women [60]. During early pregnancy, elevated levels of soluble B7-H4 (sB7-H4) are observed in women who experience preterm premature rupture of the amniotic membranes [61, 62], as well as in women at an increased risk for preeclampsia [63], when compared to women with uncomplicated pregnancies. Changes in the soluble forms of B7 molecules have been implicated in immunological alterations associated with maintenance of a healthy pregnancy and the development of preeclampsia [63, 64]. sB7-H1 and sB7-H4 have been detected in the sera of cancer patients, and their expression levels are closely linked to progression and prognosis [65,66,67].
Both early and term placental trophoblast cells have been shown to secrete B7-H1 and B7-H3 via exosomes [68]; these exosomes and similar trophoblast-derived microvesicles can be engulfed by phagocytes and serve as vehicular shuttles for paternally-inherited placental antigens that are ultimately cross-presented to maternal T cells by a variety of antigen-presenting cells [43]. Exosomal B7 molecules are also released from cancer cells. Metastatic melanoma cells release exosomes carrying PD-L1 on their surface that suppress the function of CD8 T cells and facilitate tumor growth [69]. Additionally, a high expression of B7-H3 was observed in urinary exosomes isolated from colorectal cancer patients [70]. Similarities between requirements for growth and immune privilege in cancer and pregnancy could lead to a better understanding of the maternal–fetal immune response.
Other Immune Checkpoint Modulators
Indoleamine 2,3-Dioxygenase
Indoleamine 2,3-dioxygenase (IDO) is the initial and rate-limiting enzyme that breaks down tryptophan into kynurenine [71, 72]. Since tryptophan is necessary for T cell proliferation and activation, IDO-induced tryptophan degradation functions to promote T cell suppression. T cells are further differentiated into immunosuppressive Foxp3+ T regulatory cells via kynurenine-mediated hydrocarbon receptor (AhR) activation [73, 74]. Following stimulation with proinflammatory mediators such as IFN-γ, IDO is widely expressed in various tissues of mammals. IDO exhibits particularly high endogenous activity in cells present at the maternal–fetal interface, including trophoblast cells, decidual stromal cells, decidual immune cells, and vascular endothelial cells of the chorion and decidua [75]. Emerging evidence has shown that the expression and activity of IDO differ not only among non-pregnant, normal pregnant, and pathological pregnancy conditions, but also by gestational age [76,77,78]. In normal pregnancy, IDO is involved in maternal–fetal immune tolerance and protection against pathogens. When pregnant mice carrying syngeneic or allogeneic fetuses were exposed to 1-methyl-tryptophan (1MT), an IDO inhibitor, all of the allogeneic fetuses, but none of the syngeneic concepti, were rejected. This rejection phenomenon was mediated by a single paternally inherited MHC class I loci and was fully dependent on maternal T cell activity [79]. Pregnant mice deficient in recombination activating gene 1 (RAG-1) expression, and thereby unable to develop lymphocytes, were not affected by 1MT treatment. These results strongly suggest that IDO plays a crucial role in defense of the conceptus against allogenic rejection. Subsequent studies have demonstrated that IDO eliminates pathogens through nutrient competition via tryptophan depletion [80,81,82]. IDO could also promote trophoblast invasion into the decidualized endometrium and remodeling of maternal spiral arteries, both essential to placental perfusion and fetal development [83, 84]. A decrease in the expression levels of IDO is associated with pregnancy complications such as preeclampsia and intrauterine growth restriction [77, 85,86,87]. Considering the role of IDO in cancer development, where its high expression and activity support immune escape for tumor survival [88, 89], decreased IDO levels and activity in pregnancy are likely implicated in exaggerated inflammatory responses at the maternal–fetal interface and adverse alterations in placental and fetal growth and function.
CD47
CD47 (also known as integrin-associated protein, IAP) is a ubiquitously expressed membrane glycoprotein belonging to the immunoglobulin superfamily. CD47 serves as a ligand for signal regulatory protein alpha (SIRPα, also known as CD172a), a membrane glycoprotein present mainly on macrophages [90]. CD47 − SIRPα interactions induce downstream signal activation that inhibits target cell phagocytosis. To this point, CD47 has been called a “don’t eat me” signaling molecule to characterize its interactions with SIRPα. CD47 has received significant attention in cancer research as a means for tumor cell immune evasion and is also regarded as a key determinant in transplantation success [91,92,93]. Although only a few studies on CD47 have been reported in the reproductive immunology literature, these reports suggest that CD47 may play an important role in maternal–fetal immune interactions. Notably, CD47 has been documented in extracellular vesicles (EVs) extruded from the STB of the placenta into the maternal blood [94, 95]. Since placentally-derived EVs are important mediators of intercellular communication, the presence of CD47 in these EVs could promote tolerance to the STB from which they originated and may prevent the clearance of these vesicles from maternal blood. In addition to inhibition of macrophage phagocytosis, CD47 − SIRPα interactions are also involved in suppression of adaptive immune responses. In fact, blockade of CD47 − SIRPα interactions induces dendritic cell activation and T cell priming, suggesting these interactions could help to bridge innate and adaptive immunity during pregnancy [96, 97]. Further research into the role of CD47 in immune regulation and balance at the maternal–fetal interface is certainly warranted.
Conclusion
Immune checkpoints are essential to tumorigenesis and important cancer therapeutics have been introduced that specifically target these checkpoints. Many of these same immune checkpoints appear to be involved in the immunologic interactions occurring at the human maternal–fetal interface. Alterations in the proper functioning of these immune checkpoints have been linked to early pregnancy loss, disorders of abnormal placentation such as impaired fetal growth, and hypertensive disorders of pregnancy (Table 1). Although there has been significant interest in these molecules and their interactions in human pregnancy, much remains to be learned. Their important and expanding role in cancer therapy, however, suggests that an improved understanding of their function and dysfunction during placental growth and development may offer breakthrough opportunities in the preventative and therapeutic care of women and their babies during pregnancy.
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The authors’ research is supported by grants 1RO1HD094937 from the National Institutes of Health (DJS), R21A1145071 from the National Institutes of Health (DJS, JZ), and pilot grant from the University of Missouri (SC).
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Mebane, S., Zhou, J., Choi, S. et al. Immune Checkpoint Molecules and Maternal–Fetal Immunity. Curr Obstet Gynecol Rep 13, 37–45 (2024). https://doi.org/10.1007/s13669-024-00372-3
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DOI: https://doi.org/10.1007/s13669-024-00372-3