Role of maternal–fetal immune tolerance in the establishment and maintenance of pregnancy

Abstract

Normal pregnancy is a contradictory and complicated physiological process. Although the fetus carries the human leukocyte antigen (HLA) inherited from the paternal line, it does not cause maternal immune rejection. As the only exception to immunological principles, maternal–fetal immune tolerance has been a reproductive immunology focus. In early pregnancy, fetal extravillous trophoblast cells (EVTs) invade decidual tissues and come into direct contact with maternal decidual immune cells (DICs) and decidual stromal cells (DSCs) to establish a sophisticated maternal–fetal crosstalk. This study reviews previous research results and focuses on the establishment and maintenance mechanism of maternal–fetal tolerance based on maternal–fetal crosstalk. Insights into maternal–fetal tolerance will not only improve understanding of normal pregnancy but will also contribute to novel therapeutic strategies for recurrent spontaneous abortion, pre-eclampsia, and premature birth.

Introduction

The number of infertility patients who have turned to assisted reproductive technology (ART) has recently continued to increase. More than two million ART operations are performed every year worldwide. Improved ovulation promotion strategies and culture conditions have increased the rate of high-quality embryos, but the success rate of in vitro fertilization-embryo transfer (IVF-ET) is only 40–60%.^[1] This is because successful implantation requires not only blastocyst ability to invade the endometrium but also normal maternal uterus acceptance.^[2] In a special semi-allograft, half of an embryo’s genes are from the mother and half are from the father. During normal pregnancy, the embryo can survive in the maternal uterus without being immune-rejected and relies on the mother’s immune tolerance mechanism.^[3]

The maternal–fetal immune tolerance theory was described in the 1950s. The Nobel Prize winner Peter Medawar proposed three theories to explain how the fetus as a semi-allograft can escape maternal immune system attack^[4]: (1) placental barrier theory; (2) fetal antigen immaturity theory; (3) maternal uterine immunity licensing. These three theories promoted the development of reproductive immunology and retained pivotal guiding significance. However, the rapid development of reproductive immunology yielded subsequent studies that challenged these views.

Recent studies reported that the inflammatory and immune processes during pregnancy are more similar to the immune processes related to tumor progression.^[5] Trophoblast proliferation, migration, invasion, and placental implant site neovascularization are similar to tumor cell activity, and the immune cells and cytokines at the maternal–fetal interface are similar to those of the tumor microenvironment.^[6] Successful pregnancy depends on the balance between immune activation and immune tolerance to embryonic antigens.^[7] Based on a summary of previous research results, this review elucidates the establishment and maintenance mechanism of maternal–fetal tolerance by focusing on the maternal–fetal interaction dialogue.

Maternal–Fetal Interface Composition and Function

As the microenvironment for pregnancy establishment and maintenance, the maternal–fetal interface contains various cells that can be approximately divided into three categories according to their source: embryo-derived extravillous trophoblast cells (EVTs), maternal-derived decidual stromal cells (DSCs), and decidual immune cells (DICs) [Figure 1].^[8] Nutrient exchange and metabolism are conducted between the mother and fetus. During pregnancy, the maternal–fetal crosstalk is mainly manifested in the balance between the immune rejection and immune tolerance of the maternal immune system to embryonic heterologous antigens. Accordingly, the mother does not reject the “heterologous” embryo during implantation. Maternal–fetal tolerance imbalance can lead to adverse pregnancy outcomes, such as spontaneous abortion, pre-eclampsia, and premature birth.^[9]

Figure 1.

Maternal–fetal interface cell composition. The placenta provides the interface between the mother and the fetus and mainly includes the myometrium, decidua, maternal spiral artery, villus units, and amnion. The maternal–fetal surface cell composition is complex, comprising embryo-derived EVTs and maternal-derived DSCs and DICs. EVTs mainly carry paternal antigens and participate in placenta formation through proliferation and invasion. DSCs mainly provide nutrients, and DICs secrete cytokines to maintain immune tolerance and defend against infection. The DICs mainly include dNKs, dMs, DCs, uMCs, T cells, and B cells. DCs: Dendritic cells; DICs: Decidual immune cells; dMs: decidual macrophages; dNKs: Decidual natural killer cells; DSCs: Decidual stromal cells; EVTs: Extravillous trophoblast cells; uMCs: Uterine mast cells.

Trophoblast biological functions

Fetal-derived trophoblasts differentiate along two pathways: synthetic trophoblasts are mainly involved in nutrient and metabolite transport and perform placental endocrine functions, while EVTs grow aggressively into the uterine interstitial and spiral arterial cavities, replacing the spiral arterial endothelium and causing vascular remodeling, and provide oxygen and nutrients to the fetus.^[10] Trophoblasts are the only embryonic cells that are in direct contact with maternal DICs. Trophoblast migration and invasion are key in blastocyst implantation and placenta development, which are vital in maternal–fetal immune tolerance.^[11]

Early embryo human leukocyte antigen (HLA)-G is the key to successful implantation. Decidual natural killer cells (dNKs) are cytotoxic in the absence of HLA-G.^[12] However, EVT-expressed HLA-G can inhibit dNK cytotoxic and killing effects by binding to their inhibitory receptor killer cell Ig-like receptor 2DL4 (KIR2DL4). After implantation, membrane-bound HLA-G and soluble HLA-G (sHLA-G) induce immune tolerance and promote uterine spiral artery remodeling and fetal growth.^[13] HLA-G binds to the KIR2DL4 receptor on the dNK surface and induces the upregulation of C-X-C chemokine motif ligand^[10] (CXCL10), placental growth factor, and vascular endothelial growth factor (VEGF). Cytokines such as interferon gamma (IFN-γ), VEGF, and matrix metalloproteinase 2 (MMP-2) and MMP-9 are produced via the nuclear factor κB (NF-κB) signaling pathway to promote vascular remodeling.^[14]

Recently, the role of HLA-G in clinical practice was confirmed. Low HLA-G expression affects dNK cytokine-secretion function and reduces KIR2DL4 expression, which is a possible mechanism for recurrent spontaneous abortion (RSA).^[15] Moreover, placenta-mediated pregnancy syndrome is associated with low sHLA-G levels in peripheral blood during early pregnancy.^[16] These results suggested that detecting serum sHLA-G after clinical ART might be a positive predictor of pregnancy outcome.

EVTs can promote dendritic cell (DC) secretion of the T helper 2 (Th2)-type C-C motif chemokine ligand 17 (CCL17) and interleukin-10 (IL-10), leading to decidual CD4⁺ T cell differentiation into Th2 type cells and forming a unique Th2 immune advantage at the maternal–fetal interface.^[17] Furthermore, trophoblasts secrete abundant CXCL12, which not only promotes MMP-2 and MMP-9 secretion and invasion ability but also promotes the Th2 advantage in co-culture systems by interacting with CXC chemokine receptor 4 (CXCR4, the CXCL12 receptor) on DSCs and DICs.^[18] These studies identified the dominant role of trophoblast cells in maternal–fetal interaction.

DSC biological functions

Most available studies mainly focused on fetal-derived trophoblasts, while maternal-derived DSCs, the major decidual constituent, have widely been neglected. In addition to participating in decidual nutrition supply, DSCs secrete active hormones, various cytokines and enzymes, express progesterone receptors, and regulate blastocyst implantation and placenta formation. As the two main constituent cells of the maternal–fetal interface, DSCs and EVTs are in direct contact, and their interaction is an important part of maternal–fetal immune regulation.^[19]

Previous studies confirmed that EVTs form desmosome connections with maternal DSCs, suggesting the existence of dialogue and communication between them. Such dialogue is essential for maintaining a normal pregnancy. By releasing the chemokine CCL2, DSCs promote Th2 cell IL-4 and IL-10 secretion and inhibit Th1 cell IFN-γ and tumor necrosis factor-alpha (TNF-α) secretion, thereby maintaining the Th2 immune advantage at the maternal–fetal interface.^[20] Via indoleamine 2,3-dioxygenase (IDO) and prostaglandin E2 (PGE2) action, DSCs inhibit the proliferation, toxicity, and ability of natural killer (NKs) to produce IFN-γ and T cell proliferation.^[21] Furthermore, DSC-produced macrophage inhibitory cytokine-1 (MIC-1) promotes the generation of maternal–fetal interface tolerogenic DCs and promotes IL-10 secretion.^[22] The DSC surface also expresses HLA-G and is predominant in immunomodulatory functions. Gene silencing of key DSC chemokines reduces the entry of killer T cells into the maternal–fetal interface and promotes immune tolerance.^[23] Nevertheless, DSCs also protect local decidual T cells from apoptosis.^[24] DSCs exert different immune effects on the maternal–fetal immune interaction dialogue, which is crucial to the pregnancy outcome.

DIC biological functions

DICs are the basis of maternal–fetal immune tolerance and consist mainly of specialized NK cells: CD56^brightCD16⁻ cells (~70%), T cells (~10%), and monocytes (~10%). Via special activation markers and abundant cytokine production, the maternal–fetal interface plays a local immune regulatory role different from that of the periphery, producing inherent Th2 and regulatory T cell (Treg) immune advantages.^[25] DICs regulate trophoblast growth, differentiation, and migration via paracrine effects, thus playing an important local regulatory role in maintaining a pregnancy.^[26]

The maternal–fetal interface microenvironment might also participate in the functional training of maternal immune cells. Early-pregnancy trophoblasts induce dominant Th2 and Treg differentiation at the maternal–fetal interface by regulating decidual DCs, T cells, and their interactions, which is conducive to maintaining the immune tolerance state of the maternal–fetal interface.^[17]

Innate Immune Cell Function at the Maternal–Fetal Interface

Foreign antigens first encounter the innate immune system. The innate immune system secretes cytokines and presents antigens to recruit other immune cells and activate the specific immune system. Uterine innate immune cells not only constitute the first line of immunity but also initiate and maintain pregnancy.

NK cells

dNKs are the most abundant immune cells at the early maternal–fetal interface, accounting for approximately 70% of immune cells.^[27] dNKs are mainly the CD56^brightCD16⁻ phenotype, which is characterized by low cytotoxicity and high secretory activity and differs greatly from the peripheral blood NK cells, whose main phenotype is CD56^dimCD16⁺.^[28] dNKs mainly regulate maternal uterine spiral artery remodeling and trophoblast invasion and are crucial regulators at the maternal–fetal interface.^[29] The chemokines C-C motif chemokine receptor 1 (CCR1), CCR2, and CXCR1 are involved in dNK recruitment.^[30] DSCs and EVTs produce transforming growth factor beta (TGF-β) and IL-5, promoting hematopoietic stem cell differentiation into NK cells, which clarifies why NK cells are enriched at the maternal–fetal interface.^[31]

dNKs are recruited during embryo implantation and proliferate, releasing numerous MMPs involved in decidualization.^[32] dNKs also express various cytokines, such as VEGF-A, VEGF-C, and angiopoietin 1 (ANG-1), which regulate trophoblast invasion, guide uterine spiral artery remodeling, and promote blood vessel formation in the placenta.^[33]

Excessive dNK activation leads to Th1–Th2 imbalance, which causes complications such as maternal uterine vessel thrombosis and impaired placental function.^[34] Patients with RSA exhibit severe inflammatory responses at the maternal–fetal interface, where the proportion of dNKs and IFN-γ and IL-1 receptor antagonist (IL-1RA) secretion are significantly decreased, which result in ineffective inhibition of Th17 cell polarization. Simultaneously, other decidual cells secrete large amounts of IL-6 and IL-1β to promote inflammatory cell differentiation and exacerbate inflammation, leading to maternal–fetal tolerance cessation and ultimately pregnancy failure.^[35]

Macrophages

After dNKs, macrophages are the second largest leukocyte population within the decidua, accounting for about 20–25% of the total immune cells at the maternal–fetal interface.^[36] Under granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulation, macrophages rapidly move to the endometrium and present paternal antigens to the T cells.^[37] Macrophages are generally divided into M1-type macrophages (pro-inflammatory cells that secrete IL-12, IL-23, and active nitroxides) and M2-type macrophages, mainly contributing to spiral artery remodeling and inflammation regression.^[38]

In early pregnancy, trophoblasts and DSCs recruit macrophages to the decidua. Contact with Tregs decreases the antigen-presenting function of macrophages, while immunosuppressive molecule expression and anti-inflammatory cytokine secretion are upregulated to maintain immune tolerance.^[39] Under local IL-10 regulation, macrophages gradually differentiate into the M2 type, maintain the luteal vascular network, and promote progesterone generation and fertilized egg implantation.^[40] Simultaneously, M2 macrophages also secrete TGF-β, IL-10, and IDO, which protect trophoblasts from immune attack.

In the second trimester, macrophages are mainly distributed around the endometrial blood vessels and in the myometrial basal connective tissue. In the presence of TNF-α and IL-1β, M1 macrophages increase and relax smooth muscle and inhibit uterine muscle contraction by synthesizing nitric oxide (NO). M1 macrophage numbers decrease near delivery, which reduces the NO concentration. Concurrently, CCL2 chemotaxis aggregates macrophages to the uterus, promoting macrophage secretion of inflammatory factors, such as TNF-α, and activating labor.^[41]

DCs

Although DCs represent only 1–2% of the total DICs, they are key sentinels at the maternal–fetal interface.^[42] DCs might play a dual role in early pregnancy. DCs promote immune tolerance by inducing effector T cell apoptosis and Treg proliferation; conversely, they activate T cells that drain lymph nodes as antigen-presenting cells (APC) and promote T cell immune activation.^[43]

During normal pregnancy, DC antigen presentation effectiveness at the maternal–fetal interface is weakened, and co-stimulatory molecule expression is reduced, which promotes DC differentiation into tolerogenic DCs and reduces the maternal rejection of fetal antigens.^[44] In the second trimester, DCs act as a bridge between dNKs and Tregs and control the TNF-α level secreted by T cells by regulating the L-arginine level.^[45] Furthermore, uterine DCs (uDCs) aggregate into clusters that coincide with the embryo implantation sites.^[46] Knocking out uDCs causes embryo implantation failure or absorption.^[47]

Mast cells

Uterine mast cells (uMCs) mainly colonize the myometrium and localize around decidual vessels, playing a pivotal role in embryo implantation. Under estrogen and progesterone recruitment, uMCs reach the uterus and release histamine, MMPs, tryptase, and VEGF, aiding the embryo in endometrial contact and invasion.^[48] uMCs are also associated with angiogenesis, placenta morphogenesis, and embryo development during pregnancy: uMC-deficient mice exhibited diminished spiral artery remodeling and consequently intrauterine growth restriction (IUGR).^[46]

Specific Immune Cell Functions at the Maternal–Fetal Interface

Also known as adaptive immunity, specific immunity specifically recognizes and responds to antigens. Memory cells persist after the antigens are cleared, preparing for the next rapid immune response when exposed to the same antigens. The maternal and fetal-specific immune systems tolerate each other during normal pregnancy, and abortions or preterm births occur once the balance is broken prematurely.

T cells

In early pregnancy, decidual T cells account for 10–20% of immune cells, among which CD8⁺ T cells account for 45–65%, γδ T cells account for about 20%, and CD4⁺ T cells account for 30–45%. In the third trimester, the CD4⁺ T cell proportion increases while that of CD8⁺ T cells decreases.^[49] Mature T cells specifically recognize and bind to the antigen via T cell receptors (TCR) on the surface.

CD8⁺ T cells

CD8⁺ T cells are the main group of T lymphocytes in early pregnancy, and their phenotypes are mostly memory T cells. Compared with peripheral CD8⁺ T cells, decidual CD8⁺ T (dCD8⁺ T) cells express lower perforin and granzyme B levels.^[50] Furthermore, dCD8⁺ T cells express programmed cell death-1 (PD-1) and T-cell immunoglobulin mucin 3 (TIM-3), limiting the CD8⁺ T cell proliferation induced by fetal antigen stimulation. Moreover, the decidual CD8⁺IL-10⁺ Treg subset content is significantly higher than that in peripheral blood, with high proliferation activity and cytokine secretion ability, and CD69 and CD103 upregulation indicates their important regulatory roles in immune tolerance.^[51]

γδ T cells

The γδ T cell TCR double strands are not the classic α- and β-chains but are γ- and δ-chains. γδ T cells are important in innate and adaptive immune regulation, but functional studies on γδ T cells during pregnancy are relatively lacking. In vitro experiments determined that IL-25 might promote γδ T cell IL-10 production and γδ T cell proliferation and might form a positive feedback loop to maintain the Th2 cell bias at the maternal–fetal interface.^[52] In the decidua, γδ T cells secrete the anti-inflammatory cytokines IL-10 and TGF-β to protect trophoblasts from rejection.^[53]

CD4⁺ T cells

CD4⁺ T cells are more important in pregnancy than CD8⁺ T and γδ T cells and are mainly divided into two groups^[9]: one represented by Tregs and Th2 cells that play an immunosuppressive and regulatory role, and another represented by Th17 and Th1 cells that exert immune effects. The two groups interact to ensure relatively balanced secreted cytokines and maintain normal pregnancy together. Weakening the inhibitory effect, i.e., increasing the Th1–Th2 and Th17–Treg ratios, leads to serious consequences such as infertility, miscarriage, and premature birth.^[54]

Tregs

As early as 2004, scientists demonstrated that Tregs participate in maternal–fetal immune tolerance and have a negative regulatory function. Tregs specifically express forkhead box protein 3 (FoxP3) and exert immunoregulatory effects mainly through two mechanisms: (1) indirectly by secreting cytokines, such as IL-10, TGF-β, IDO, and hemeoxygenase-1 (HO-1). IL-10 and TGF-β are anti-inflammatory factors, while HO-1 upregulates IL-10, TGF-β, and cytotoxic T-lymphocyte antigen 4 (CTLA-4) expression^[55] and (2) directly regulating the contacted effector T cells by releasing granzymes, perforins, or transmitting inhibitory signals.^[47]

Recent studies reported that Tregs are amplified in maternal peripheral blood, the decidua, and fetal umbilical cord blood during pregnancy, indicating an important role in maternal–fetal immune regulation.^[56] The absence of Tregs can lead to pregnancy failure: women with RSA have relatively low Treg levels,^[57] and animal experiments demonstrated that knocking out Tregs was not conducive to maintaining pregnancy in mice.^[58] Clearly, Treg immunosuppressive function is important in embryo implantation and pregnancy maintenance, but Treg function in the third trimester remains unclear.

Th cells

Th cell-secreted cytokines cooperate to maintain the immune tolerance microenvironment. Several studies confirmed that the Th1–Th2 cell balance is a mechanism that maintains maternal–fetal tolerance: Th1 cells produce IL-2, TNF-α, and IFN-γ, which promote macrophage production of a strong delayed immune response and cause inflammation and tissue damage to inhibit embryo implantation; Th2 cells secrete IL-4, IL-5, IL-6, IL-10, IL-13, and TGF-β2, which suppress immune inflammation and facilitate embryo implantation.^[59] In an altered Th1–Th2 cytokine ratio, Th2 cells are dominant, and Th1 cells are temporarily inactivated and are the determinants of fetal survival in the uterus. The maternal–fetal interface of a normal pregnancy mouse model presented a typical Th2 immune advantage. Overturning this advantage significantly increased the incidence of spontaneous abortion. Injecting pregnant mice with the Th2 cytokine IL-10 or antagonists of the Th1 cytokine TNF-α inhibited lipopolysaccharide (LPS)-induced pregnancy failure.^[60]

Naïve CD4⁺ T cells differentiate into Th17 cells when exposed to a microenvironment containing inflammatory cytokines such as IL-6, IL-1β, and TNF-α.^[61] Th17 cells secrete inflammatory cytokines such as IL-17A, IL-17F, IL-21, IL-22, and TNF-α, which are generally considered the culprits in mediating inflammatory and autoimmune diseases, as opposed to maternal–fetal immune tolerance.^[62] Retinoid-related orphan receptor γt (RORγt) is a Th17 cell-specific transcription factor involved in regulating Th17 cell proliferation and differentiation and promoting IL-17A/F translation and expression. Mice lacking the RORγt gene have decreased Th17 cell numbers.^[63] FoxP3 directly or indirectly acts on RORγt to exert negative immune regulation, inhibit IL-17 mRNA transcription, and thus inhibit Th17 cell secretion of inflammatory cytokines.^[64] Th17 cells promoted EVT invasion and inhibited EVT apoptosis by secreting IL-17,^[65] which increased progesterone secretion in human trophoblast JEG-3 cells.^[63] However, excessive activation and increased Th17 cell numbers lead to pregnancy complications such as RSA, pre-eclampsia, and premature birth.^[66] Although Th17 cells are unfavorable for maintaining maternal–fetal tolerance, their ability to remove foreign microorganisms plays an important protective role in the uterus.^[67]

In summary, Th1 and Th2 cells, RORγt⁺ Th17 cells, and FoxP3⁺ Tregs are closely related. Th1–Th2 and Th17–Treg are in a dynamic equilibrium state through gene regulation and cytokine interactions, which is extremely critical in maintaining normal pregnancy and delivery.^[68]

B cells

As an important segment of specific immunity, B cells have multiple functions such as antibody synthesis, antigen presentation, and immune regulatory factor secretion.^[69] During pregnancy, B cells participate in regulating immune tolerance and downregulate the effector immune response mainly by secreting IL-10 and reducing TNF-α secretion by CD4⁺ Th cells, thereby reducing humoral immune response damage to embryonic antigens.^[70] Fetal antigens can induce B cell apoptosis under human chorionic gonadotropin (hCG) action. The basal decidua of preterm pregnant women contained a high proportion of CD20⁺CD70^– B cells, which led to decreased expression of progesterone-induced blocking factor 1 (PIBF1) and IL-33 secretion, which might have caused premature birth.^[71] As B cell distribution changes are associated with preterm birth, more studies are needed to determine the key role of B cells during pregnancy. Furthermore, B cell distribution and characteristics in early decidual tissues have not been reported thus far.

Treating the Cause of Maternal–Fetal Immune Tolerance

According to the earlier information, implantable or pregnancy immune system imbalance might lead to implantation failure or abortion. Therefore, immunosuppressive or immunomodulatory agents can help prevent immune attacks. Initially, research focused on steroids such as prednisolone or intralipids to treat abortion, thereby inhibiting the activity of most immune cells. Subsequently, intravenous immunoglobulins (IVIGs) were introduced and involved various mechanisms.^[72] New and specific strategies are currently being developed, such as monoclonal antibodies and cytokines. More recently, tacrolimus and cyclosporine, which are used to prevent transplant rejection, have been used as immunosuppressors to modulate immune responses.^[73]

In early pregnancy, the immunosuppressant cyclosporine A promotes increased EVTs at the maternal–fetal interface and promotes EVT migration and invasion and embryo implantation. Concurrently, cyclosporine A enables Th2-type cytokine dominance at the maternal–fetal interface.^[74] Clinical studies reported that low-dose cyclosporine A corrected over- or underexpressed cytokines at the embryo transfer window, which was conducive to embryo implantation and increased the live birth rate of unexplained RSA (URSA).^[75] Low-molecular-weight heparin promoted trophoblast proliferation, invasion, and vascular remodeling. Currently, it is believed that low-molecular-weight heparin will not enter the fetus through the placenta or cause adverse effects such as bleeding and osteoporosis in pregnant women, and significantly reduces uterine artery blood flow resistance in URSA patients.^[76] Aspirin inhibits platelet aggregation, increases prostacyclin levels, has anticoagulant effects, and low doses do not cause fetal malformation. Compared with aspirin alone, low-molecular-weight heparin combined with aspirin significantly increased the live birth rate without increasing the risk of intrapartum and postpartum hemorrhage.^[77] However, some studies reported that aspirin alone or together with heparin had no beneficial effect on the live yield of URSA.^[78]

Vitamin D regulates the maternal–fetal immune tolerance microenvironment and facilitates embryonic development, such as enhancing the transition to Th2 cells and regulating immune cell differentiation and cytokine secretion. Vitamin D deficiency is associated with miscarriage, and adequate vitamin D levels might be important for preventing recurrent miscarriage.^[79] Activated lymphocytes secrete PIBF, which induces a Th2 immune response at the maternal–fetal interface and inhibits NK cell activity. Progesterone activates lymphocyte synthesis of PIBF for immune regulation and is key in fetal protection.^[80] Dydrogesterone is involved in fetal protection and promotes uterine blood flow perfusion and endometrial receptivity.^[81]

Lymphocyte immunotherapy (LIT), IVIGs, and the use of growth factors such as GM-CSF also aids the improvement of URSA pregnancy outcomes.^[82] Clinical data demonstrated that the abortion rate decreases after immunotherapy, and pregnancy and live birth rates increase regardless of whether the blocking antibody turns positive.^[83] However, these treatment options remain controversial.

Myeloid-derived suppressor cells (MDSCs) are a population of immature and heterogeneous bone marrow cells with immunosuppressive functions. Normal pregnancy features numerous MDSCs, which can interact with other immune cells, especially NK cells, DCs, and Tregs, to participate in immune regulation combined with their immunosuppressive effect.^[84] Given the close relationship between MDSCs and maternal–fetal immune tolerance, it is speculated that MDSCs might present a new immunotherapeutic strategy for treating pathological pregnancies.

Conclusions

The decidualized endometrium and developing trophoblast cells jointly constitute the maternal–fetal interface, where a large fraction of immune cells gather to regulate maternal–fetal immunity and protect the embryo from rejection by the mother [Figure 2]. Pregnancy initiation depends on the innate immune cells and Tregs: the former promotes angiogenesis and maintains luteal integrity, providing nutritional conditions for embryo implantation; the latter suppresses the immune response through immune regulation and creates an immune microenvironment for embryo implantation. Establishing an immune tolerance microenvironment and abundant blood supply are the prerequisites for pregnancy maintenance. Any deviation from this process might lead to abortion or premature birth.

Figure 2.

Schematic diagram of maternal–fetal immune tolerance. Immune tolerance starts from paternal antigens carried by sperm coming into contact with the maternal system. The paternal antigens are presented to the DICs by DCs, leading to the proliferation and differentiation of antigen-specific Tregs. The Tregs then migrate to the maternal–fetal interface and reduce dNK cytotoxicity by secreting the anti-inflammatory cytokines TGF-β and IL-10, thereby playing an immune tolerance role and maintaining normal pregnancy. DCs: Dendritic cells; DICs: Decidual immune cells; dNK: Decidual natural killer; IL-10: Interleukin-10; TGF-β: Transforming growth factor beta.

Maternal–fetal immune tolerance is the reproductive immunology focus and hotspot. Despite the rapid development, ART cannot address pregnancy failure caused by maternal–fetal regulatory dysfunction. Further exploration of the maternal–fetal immune regulation network will herald breakthroughs for diagnosing and treating pregnancy-related diseases and promote the rapid progress of perinatal medicine basic theory and technology. Clearly, such research achievements in this field might also aid the therapeutics of autoimmune diseases and tumors, which hold important academic value.

Funding

This study was supported by the Key R & D Projects of Shaanxi Province (No. 2021SF-005) and the Youth Independent Innovation Project of Tangdu Hospital (No. 2023BTDQN020).

Conflicts of interest

None.