|Year : 2020 | Volume
| Issue : 1 | Page : 53-59
Innate lymphoid cells in normal pregnancy and pregnancy-Related diseases
Cheng-Jie Wang1, Yi Yu2, Ming-Qing Li3, Wei-Rong Gu2
1 Laboratory for Reproductive Immunology, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
2 Department of Obstetrics, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
3 Laboratory for Reproductive Immunology, Institute of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital of Fudan University; Laboratory for Reproductive Immunology, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, Shanghai 230032, China
|Date of Submission||09-Jan-2020|
|Date of Decision||31-Jan-2020|
|Date of Acceptance||03-Mar-2020|
|Date of Web Publication||2-Apr-2020|
Laboratory for Reproductive Immunology, Institute of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Lane 1326 Pingliang Road, Shanghai 200082
Department of Obstetrics, Obstetrics and Gynecology Hospital of Fudan University, 419 Fangxie Road, Shanghai 200011
Source of Support: None, Conflict of Interest: None
Innate lymphoid cells (ILCs) are a group of lymphocytes without diversified antigen receptors encoded by gene rearrangement on T and B cells. ILCs, which are tissue-resident innate immune cells, expressed particularly in the mucosa or the barrier surface, contribute to the formation of lymphoid organs, the maintenance of tissue homeostasis, and the regulation of antimicrobial defenses. It has been recently reported that ILCs were enriched at the maternal–fetal interface. During a successful pregnancy, the maternal immune system must tolerate a fetus as an allograft. With the new defined of ILCs, a number of studies have shown that three types of ILCs are involved in embryonic development and pregnancy maintenance as well as the occurrence and development of pregnancy-related complications. This article reviews the types and roles of ILCs in normal pregnancy and pregnancy-related diseases.
Keywords: Immune, Innate Lymphoid Cells, Maternal–Fetal Interface, Pregnancy
|How to cite this article:|
Wang CJ, Yu Y, Li MQ, Gu WR. Innate lymphoid cells in normal pregnancy and pregnancy-Related diseases. Reprod Dev Med 2020;4:53-9
| Introduction|| |
Pregnancy refers to the gestation period beginning with the fertilization of mature ova, through the growth and development of embryos and fetuses in the uterus, and finally to the delivery of fetuses from the mother. As an allograft, the fetus is recognized but not rejected by the maternal immune system, which is called maternal–fetal immune tolerance. Such tolerance is generally characterized by the anatomical separation of the mother and the fetus, the low antigenicity of the fetus, and the immunological inertia of the mother's immune system. At present, it is known that normal embryonic development in utero occurs because of both fetal and maternal regulation, and there is a complex immune mechanism, which is regulated by a network of maternal hormones, immune cells, cytokine, adhesion molecules, and trophoblast cells. The maternal–fetal interface is a special immune microenvironment mainly composed of fetal trophoblast cells, maternal decidual stromal cells, decidual glandular epithelial cells, and immune cells.
Innate lymphoid cells (ILCs) are innate immune cells previously in the form of lymphocytes and have been discovered in recent years. ILCs colonize tissues, especially mucosal tissues and those found on barrier surfaces. It is a heterogeneous group of cells, the biological function of which falls between that of innate immune cells and adaptive immune cells; therefore, they play an important role in lymphatic organ formation, tissue reconstruction, and antimicrobial immunity. In 2013, Spits et al. proposed a family of cells with the following three properties: the absence of recombination-activating gene dependent rearranged antigen receptors, a lack of myeloid and dendritic cell phenotypical markers, and the presence of lymphoid morphology to be classified as ILCs. Based on the cytokines they express and the transcription factors regulating their differentiation and function, these cells are divided into the following groups: ILC1, ILC2, and ILC3.
| Innate Lymphoid Cells|| |
The immune system is divided into two categories: the innate immune system and the adaptive immune system. The innate immune system has a wide range of effects, no specific response, rare immune memory, and shows primary immune response, which is often the prerequisite for the latter, whereas the adaptive immune system is the opposite. Previously, it was long believed that these two systems were distinct because of their different origins and effects and that natural killer (NK) cells were the only innate immune cells in the lymphoid lineage. However, it has recently been found that there are many types of ILCs in both mice and humans.,, As innate immune cells, ILCs exist in mucosal and barrier tissues without antigen-specific recognition receptors, including B-cell receptor or T-cell receptor. Similar to T and B lymphocytes, ILCs have lymphocyte forms, originate from common lymphoid progenitor cells, and mediate adaptive immune-related functions and thus are an important bridge between the two parts of the immune system. Therefore, ILCs have become a focus of research in the past decade.
Origin and differentiation
On differentiation of hematopoietic stem cells, ILCs are differentiated into different phenotypes according to their transcription factor, which is an inhibitor of DNA binding 2 (ID2), and the influence of different cytokines, such as interleukin (IL)-7, IL-15, IL-23, and IL-25. To determine the origin of ILCs, some scholars have studied the evolution of lower vertebrates and found that the cytokine family of ILCs in mammals essentially did not exist before the evolution of maxillary fish, but the specific origin is still unclear.
In recent years, further research on ILCs has shown that these cells differentiate from common lymphoid progenitors into common innate lymphoid progenitors, which then differentiate into either NK cell precursors (NKPs) or common helper innate lymphoid progenitors (CHILPs). NKPs transform into NK cells through the t-box transcription factor (t-bet) and eomesodermin (Eomes). CHILPs can differentiate into lymphoid tissue inducer progenitors (LTiPs) and ILC precursors (ILCPs). LTiPs give rise to lymphoid tissue inducer (LTi) cells under retinoic acid receptor-related orphan receptor γt (RORγt) and the thymocyte selection-associated high-mobility group box protein. ILCPs then differentiate into ILC1s under the action of t-bet NFIL3 and RUNX3; ILC2s under the action of RORα, Bcl11B, GATA3, and GFI1; and ILC3s under the action of RORγt, aryl hydrocarbon receptor (AHR), and ID2.
ILCs are commonly divided into ILC1s, ILC2s, and ILC3s according to the expressed cytokines and the transcription factors that regulate differentiation and function. Depending on the transcription factor t-bet as it pertains to both development and function, ILC1s generally secrete interferon gamma (IFNγ), including NK cells and noncytotoxic ILC1s. ILC2s, also known as natural helper cells, express the transcription factor GATA-binding protein 3 (GATA3). ILC3s depend on RORγt, including both LTi and non-LTi ILC3s. Natural cytotoxicity receptors (NCRs) are unique markers to adjust the toxicity and specific cytokines of the cells. Depending on whether NCR is expressed, ILC3s without LTi are further divided into NCR − ILC3s and NCR + ILC3s.
In addition, despite the lack of specific antigen recognition receptors, ILCs have much in common with the development and function of T lymphocytes and thus are also known as mirror cells. ILCs can be divided into NK cells with strong killing activity, such as CD8+ killer T cells, and helper ILC cells with no or weak killing activity, such as CD4+ helper T cells. Of the helper ILCs, type 1 T helper (TH1) cells mirror lamina propria-resident ILC1 and intraepithelial ILC1 cells, TH2 cells mirror ILC2 group cells, and TH17 cells mirror NCR + ILC3 and NCR – ILC3 cells.,
NK cells and LTi cells were discovered in 1975 and 1992 and were classified as ILC1s and ILC3s, respectively, according to transcription factors and secreted cytokines. Recently, Vivier's review in cell suggested dividing ILCs into five categories (NK cells, ILC1s, ILC2s, ILC3s, and LTi cells), because NK and LTi cells have different functions and sources from the other ILC cells of the same classification.
Function and plasticity
According to classical classification, ILC1s produce IFNγ after the stimulation of IL-12 and IL-18, which play roles in viral bacterial infection and chronic inflammation, respectively. After the stimulation of IL-25, IL-23, and thymic stromal lymphopoietin, ILC2s play roles in antiparasite infections, allergic diseases, respiratory inflammatory responses, and metabolic homeostasis  by releasing IL-5, IL-13, and other cytokines. ILC3s can express IL-17A and/or IL-22 after stimulation, such as IL-1β and IL-23, where LTi is necessary for lymphoid tissue development, whereas non-LTi ILC3s play roles in intestinal humoral immunity,, extracellular immunity, and chronic inflammation.
ILC plasticity is determined by the cytokine environment. ILCs can switch between fully polarized subunits to quickly adapt to changes in the environment. After the costimulation of IL-12 and IL-18, the NCR + ILC3 RORγt expression in the cells decreases, and T-bet expression is upregulated, thus differentiating into ILC1s., In contrast, AHR has been shown to be a transcription factor that prevents IL-1R1hi ILC3s from differentiating into NK cells.
| Innate Lymphoid Cells in Normal Pregnancy|| |
Fetal extravillous trophoblast (EVT) cells invade the decidua, where they encounter the complex environment of the immune cells. Abundant evidence has proved that immune cells play an important role in regulating trophoblast cell invasion and spiral artery reconstruction. According to a report, in both mice and humans, ILC1s, ILC2s, and ILC3s exist in the uterus both before and during pregnancy. In the human decidua, ILC1s, ILC3s, and LTi cells are found in large numbers in the first trimester of pregnancy, whereas ILC2s are found in the third trimester.
Innate lymphoid cell 1s
Natural killer cells
Several studies have shown that NK cells, which were first identified in the ILC family, help induce immunosuppression, neovascularization, and tissue construction.,,, In humans, NK cells are defined as a group of lymphocytes that express CD56 but lack CD3. There are two types of NK cells in the peripheral blood: cytotoxic and regulatory. The former present CD56dim, which accounts for 90% of the total circulating NK cells, and the latter present CD56bright.
Uterine endometrial and placenta implantation site decidual NK cells (uterine NK [uNK] cells) present CD56bright and account for approximately 70% of the total lymphocytes in the decidua of early pregnancy. Unlike the regulatory NK cells in the peripheral blood, uNK cells have a large number of particles in the cytoplasm., uNK cells that are observed in small numbers increase rapidly around the time of implantation and are distributed in areas invaded by the trophoblast stroma of the embryo, primarily in the basal layer of the decidua, so they are considered to have an important relationship with embryo implantation. Recent studies have found that uNK cells do not exhibit cytotoxicity but produce cytokines and growth factors and regulate cell function through binding class I human leukocyte antigen (HLA) molecules on the surface of trophoblast cells and activating receptors.
Among them, the source of decidual NK (dNK) cells may be progenitor cells of CD34+ in situ or may be differentiated from immature NK cells in the endometrium or those that migrated from peripheral NK cells ,,, after the interaction of CXCR4 and its ligand CXCL12. dNK cells have poor cytosolubility and induce neovascularization tissue remodeling and placenta formation by releasing chemokines or cytokines, such as transforming growth factor-beta (TGF-β), instead of IFN-γ. In cases of abnormal pregnancy, TGF-β injection can improve the outcome of toxoplasma infection through the cytotoxicity of dNK cells mediated through the NKD2D/DAP10 pathway. dNK cells also receive major histocompatibility complex (MHC) molecular guidance from the mother. Human chorionic trophoblast cells express HLA-G and HLA-E, which are the major nonclassical MHC-I molecules present in the maternal–fetal interface. HLA-E can bind to NKG2A, which is the inhibitory receptor on NK cells. HLA-G also plays a regulatory role in multiple effects; for example, it has the same inhibitory effect as HLA-E, inducing the immune tolerance of DC cells and promoting the secretion of cytokines by NK cells, and the angiogenesis factor. It has also been reported that HLA-F signals through NK cell receptors to regulate the immune system during pregnancy and in cases of infection and autoimmunity. Endometrial stromal cells undergo decidualization under the action of ovarian hormones during pregnancy, whereas dNK cells secrete IL-25 to further promote decidualization. Trophoblast cell invasion was inhibited and spiral artery remodeling was delayed in NK cell-deficient mice, but there is no significant difference in progeny survival and growth. This is consistent with previous findings that indicate that the onset of trophoblast invasion usually coincides with the decrease of NK cells in the uterus. However, some scholars believe that it is the depletion of NK cells that leads to normal spiral artery reconstruction and placental function recovery in fetal/neonatal alloimmune thrombocytopenia. Some scholars believe that dual mesenchymal stem cells can regulate the function of dNK cells through the interaction between collagen and LAIR1. It has been further verified that the JAK-STAT pathway and its downstream transcription factors, T-bet and Helios, were involved in the interaction of collagen/lair-1 to regulate dNK function; thus, it has been speculated that it contributes to the maintenance of maternal and fetal immune tolerance. It has been reported that in humans, dNK cells trained during pregnancy help reduce the incidence of complications in the subsequent pregnancy, but this experiment still needs to be verified in disease models.
Other Group 1 innate lymphoid cells
Fu et al. found unconventional NK cells in the maternal–fetal interface that were CD49a + Eomes + subsets, whose transcription factor is Nfil3 instead of T-bet. The subgroup secretes growth-promoting factors (GPFs), including pluripotent phosphorus and bone glycoprotein. HLA-G interacts with immunoglobulin-like transcript receptor-2 to stimulate NK cell subsets to secrete GPFs.
During the early stages of pregnancy, other group 1 ILCs secreting IFN-γ were also detected in mice uteruses, but their number was small. NK cells depend on the expression of transcription factor Eomes, the expression of which is determined by Nfil3. In Nfil3 knockout mice, researchers found that ILC1 cells were not affected but did increase. It was indicated that non-NK group 1 ILCs existed in decidua. Furthermore, two types of CD56+ lymphocytes can be detected in the human decidua during early gestation: Lin − CD56+ CD94− CD127− CD117− T-bet + Eomes +, which express the molecule CD103, and Lin − CD56+ CD94− CD127− CD117− T-bet + Eomes −. It was found that ILC1s were more abundant in the second pregnancy, which was possibly due to the high expression of CXCR6+ in the ILCs during the second pregnancy, whose ligand is CXCL16 and is expressed by trophoblast cells, driving ILC1 expansion and colonization during pregnancy.
Innate lymphoid cell 2s
ILC2s are rarely detected in human or mouse endometria or in mouse decidua,, whereas the content of ILC2s and ILC2-like cells is relatively high in the uterine muscle layer during pregnancy, particularly in mice in the mid-pregnancy to term. The ILC2-like cells were a new subgroup of cells, which were detected as CD45+ Lin − Thy1.2+ RORγt − NKp46− KLRG1+, without GATA3 expressed by traditional ILC2s. In addition, the abundance of ILC2s in the decidua during pregnancy is very low, and these remaining uILC2s may expand through homeostasis, filling the space left by the severe reduction of uNK cells in Nfil3−/− knockout mice. A recent study found that ILC2s in preterm or term decidua is the most abundant group of ILCs and may be the type of Th2 cells to produce cytokines, such as IL-4, IL-5, and IL-13, and play an important role in achieving homeostasis. Combined with the study on preterm placental pathology, it was found that this subgroup of cells also has a certain pro-inflammatory function.
Innate lymphoid cell 3s
uILC3s are present in the human endometria and decidua and can also be detected in the both primitive uteruses and the endometria and myometria of mice during the mid-pregnancy. NCR + ILC3 and LTi cells in the ILC3 group can be detected in humans. It was confirmed that these two ILC3 groups can establish functional interactions with stromal cells, and LTi cells can differentiate into NCR + ILC3 cells and have little effect on NK cell generation. However, recent studies on tonsil mucosal immunity have found that AHR inhibition in tonsil ILC3s can induce NK cell differentiation, revealing a close correlation between ILC3s and NK cell differentiation. In AhR −/− knockout mice, the uNK cells that produce IFN-γ are abnormally differentiated. Unlike other tissues, the maturation and development of ILC3 cells in utero is not dependent on the expression of the transcription factor Nfil3.In vivo, uILC3s were mainly uLTi cells and NCR − cell groups. Regarding the lack of NCR + ILC3s, researchers speculate that this is due to the fact that the group of cells originated from the NCR − ILC3s and were absent from this differentiation pathway in mice. Other scholars have found that NCR + ILC3s and neutrophils exist simultaneously in decidual tissues, and their possible cross-expression may play a role in the early stages of pregnancy. The latest study has determined that uILC3s are highly expressed at inhibitory checkpoints PD-1 and TIM-3 and can produce IL-22, IL-8, TNF-α, and other cytokines under the inducement of IL-23. Meanwhile, a high expression of PD-L1 can be found on intermediate EVT, suggesting that the PD-1/PD-L1 interaction regulates the function of uILC3s and mediates the tolerance of maternal and fetal immune systems.
| Innate Lymphoid Cells in Pathological Pregnancy|| |
In addition to infectious diseases and autoimmune diseases during gestation caused by secondary immune responses, pathologic pregnancy is common; the main pathogenic factors and primary malfunctions of the maternal–fetal immune interface are recurrent abortion, preterm delivery, preeclampsia, and intrauterine growth restriction. It has been found that immune cells are involved in the misrecognition and rejection of the fetal antigen as a semi-allograft, the dysfunction of placental blood vessel remodeling, and the decreased supporting effect of trophoblast cells and stromal cells. As types of immune cells, ILCs not only play the role of mirror cells to generate corresponding cytokines but also directly participate in the pathophysiological process of the abovementioned diseases.
Recurrent spontaneous abortion
Studies have shown that pregnancy loss in patients who experience recurrent abortion is associated with increased peripheral NK cells in the blood., Clinical studies have further demonstrated that the proportion of CD56dim CD3− CD16+ NK cells in the uterine decidua of these patients was significantly higher than in the normal group, and the increased proportion was positively correlated with pregnancy failure., Other studies have shown that miR-34a-3p/5p, miR-141-3p/5p, and miR-24 in decidual NK cells are associated with recurrent miscarriages of unknown origin. Tim-3-galactin-9 signal transduction in peripheral NK (pNK) cells plays an important protective role in the early stages of pregnancy, and Tim-3 abundance in pNK cells is a potential biomarker for the diagnosis of recurrent abortion. In addition, recurrent abortion patients with increased pNK had significantly increased infection rates of Gardnerella vaginalis and Gram-negative anaerobic bacteria, making them more susceptible to colonization by the abovementioned flora. In mice that experienced recurrent abortion exposed to lipopolysaccharide, the uNK and uILC3s increased; meanwhile, the ratio of uILC1s to uILC2s decreased significantly, which may indicate an immune response role through upregulated IL-17a and IFN-γ along with downregulated IL-5.
CD56bright uNK cells were nearly absent in full-term and preterm pregnant women, but CD56dim cells were expressed to a larger extent in the decidua and villi of patients with idiopathic preterm delivery. The content of ILC2s was highest in the decidua of women in premature and full-term pregnancy. The proportion of ILC2s in the decidua basalis of premature pregnant women increased compared with that of full-term pregnant women, and the proportion of ILC3s in the decidua parietalis increased. Furthermore, the increased expression of ILC2s was correlated with chronic placental inflammation, suggesting that ILC2s are involved in the formation of the chronic inflammatory microenvironment in the pathological process of preterm delivery. It is indicated that the subsets of CD56dim uNK cells, ILC2s, and ILC3s may be involved in the pathogenesis of preterm labor.
CD56+ NK cells were significantly reduced in the decidua of women with preeclampsia compared with those experiencing a normal pregnancy. Moreover, the cytokines IL-12 and IL-15 produced by NK cell activation in serum were significantly increased. In the RUPP rat model, NK cell depletion significantly reduced uterine perfusion pressure, mean arterial pressure, inflammation, and incidence of intrauterine growth restriction, indicating cytolysis destruction. NK cells play an important role in the progression of preeclampsia pathological physiology. The dNK culture supernatant with a normal uterine artery resistance index (UARI) damages the stability of the endovascular-like tube structure in the matrix gel and induces the apoptosis of vascular smooth muscle and endothelial cells partly through the Fas pathway, which is of great significance in vascular remodeling. In addition, compared with patients with high UARIs, the dNK cells in pregnant women with normal UARIs were better able to induce endothelial intercellular adhesion molecules-1 and TNF-α and highly expressed hepatocyte growth factor to promote the invasion of trophoblast cells. These results suggest that dNK cells mediate the dysfunction of vascular remodeling and trophoblast cell invasion in a condition of endothelial injury similar to preeclampsia. In the peripheral blood of patients with preeclampsia and other pregnancy complications, the increase of IL-17 is unrelated to Th cell population but is associated with ILC3s.
Intrauterine growth restriction
How ILCs pertain to intrauterine growth restriction has rarely been studied. It has been reported  that the subsets of CD49+ Eomes + NK cells in the maternal–fetal interface can secrete GPFs. If the subsets of these cells are reduced, fetal development will be impaired, and fetal growth will be restricted. The induced adoptive transfer of CD49+ Eomes + NK cells can reverse the impaired outcome of fetal growth and improve the restrictive nutrients in the uterine microenvironment.
| Prospect and Outlook|| |
In the last decade, the discovery of ILCs, a population of immune cells, has led to new insights into the processes of immune cells necessary for successful pregnancy and fetal development [Figure 1]. ILCs in the maternal–fetal interface may be involved in the process of placenta implantation, the remodeling of spiral arteries, and mucosal immunity. In particular, the functions of ILCs in tissue reconstruction and the maintenance of homeostasis during implantation play an important role in maintaining pregnancy and maternal–fetal immune tolerance. The dysfunction of interaction between ILCs and other cells of decidua tissue is a possible cause of pathological pregnancy and adverse fetal outcomes. Therefore, it is very important to study the interaction mechanisms of ILCs with other immune cells, specific molecular pathways in pathological pregnancy, and the plasticity between ILC families. Intravenous immunoglobulin (IVIG) has been identified as a possible treatment option for infants with low birth rates and increased NK cells prior to pregnancy, and IVIG has also been reported to have an effect of recurrent abortion and recurrent reproductive failure with amplified circulating NK and/or NKT-like cells. Collectively, to explore the ILCs' manipulation in innovative therapies, further study should be move on the agenda to discover the specific network and roles in the fetal-maternal interface about the new defined ILCs.
|Figure 1: Roles and effects of innate lymphoid cells in normal and pathological pregnancy|
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Financial support and sponsorship
This work was supported by grants from the National Natural Science Foundation of China (No. 81801469 and 81971408).
Conflicts of interest
There are no conflicts of interest.
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