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 Table of Contents  
Year : 2019  |  Volume : 3  |  Issue : 3  |  Page : 165-169

Role of decidual natural killer cells at the Maternal–Fetal interface during pregnancy

1 NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, China
2 Department of Gynecology of Integrated Traditional Chinese and Western Medicine, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200011, China
3 NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai 200011, China

Date of Submission10-Jul-2019
Date of Web Publication27-Sep-2019

Correspondence Address:
Hai-Yan Wang
Department of Gynecology of Integrated Traditional Chinese and Western Medicine, Hospital of Obstetrics and Gynecology, Fudan University, No. 128, Shenyang Road, Shanghai 200011
Ming-Qing Li
NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Hospital of Obstetrics and Gynecology, Fudan University, No. 1326, Pingliang Road, Shanghai 200011
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2096-2924.268161

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Pregnancy is a complicated process with intricate cell-to-cell crosstalk and immune regulation. Decidual natural killer (NK) cells account for 50%–70% of decidual immune cells in early pregnancy, suggesting that they play important roles in various events, such as embryo implantation and vascular remodeling. Many studies have shown that decidual NK cells interact with other cells either through direct contact or the secretion factors such as cytokines and chemokines. Hence, this review aimed to present the phenotypic characteristics, classification, and functions of decidual NK cells at the maternal–fetal interface during pregnancy.

Keywords: Decidual Natural Killer Cells; Maternal–Fetal Immune Tolerance; Vascular Remodeling

How to cite this article:
Yang SL, Wang HY, Li DJ, Li MQ. Role of decidual natural killer cells at the Maternal–Fetal interface during pregnancy. Reprod Dev Med 2019;3:165-9

How to cite this URL:
Yang SL, Wang HY, Li DJ, Li MQ. Role of decidual natural killer cells at the Maternal–Fetal interface during pregnancy. Reprod Dev Med [serial online] 2019 [cited 2020 Feb 23];3:165-9. Available from: http://www.repdevmed.org/text.asp?2019/3/3/165/268161

  Introduction Top

Preparing for pregnancy, the endometrium transforms into the decidua to allow embryo implantation and support the growth of the placenta under the effects of progesterone and estrogen. The maternal–fetal interface shows a dynamic balance between immune tolerance and immune activation. On the one hand, adequate defenses are needed against pathogenic infections, but on the other hand, excessive activation of the immune system may lead to the rejection of the embryo, which is a semiallograft for maternal immune system.[1] The immune microenvironment at the maternal–fetal interface is regulated precisely during pregnancy, and it involves various cells including trophoblasts; decidual stromal cells; vascular endothelial cells; and immune cells, such as macrophages, T cells, dendritic cells, and natural killer (NK) cells. Decidual NK cells are the most abundant component of decidual immune cells in early pregnancy and have been demonstrated to play important roles in the maintenance of immune tolerance at the maternal–fetal interface, remodeling of decidual vessels, and regulation of the biological behavior of trophoblasts. This review presents the basic characteristics of decidual NK cells and their roles at the maternal–fetal interface.

  Basic Characteristics of Decidual Natural Killer Cells Top

Phenotype of decidual natural killer cells

According to the expressions of CD56 and CD16, NK cells in human can be divided into the following two groups: CD56bright CD16 and CD56dim CD16+.[2] In the peripheral blood, >90% of NK cells are CD56dim CD16+, which mainly act as killer cells to prevent pathogenic infection, have high cytotoxicity, and can rapidly secrete a large amount of interferon-gamma (IFN-γ) when activated. NK cells at the maternal–fetal interface are markedly different from those in the peripheral blood. They account for 50%–70% of all immune cells in early pregnancy, and this proportion is greater than that of NK cells in the peripheral blood. In addition, decidual NK cells are mainly CD56bright CD16, which have a high capacity to secrete various cytokines and chemokines and have regulatory effects on different types of surrounding cells.[3],[4] Decidual NK cells express various tissue-resident markers, such as CD9, CD69, and CD49a,[5],[6] and adhesion molecules, such as CD9, CD62L, and α-1 integrin,[7] which might contribute to their accumulation. Although decidual NK cells contain large amounts of lysozymes, such as perforin and granzyme,[8] they have very low cytotoxicity.[9] Furthermore, decidual NK cells highly express killer-cell immunoglobulin-like receptors (KIRs) and NKG2A, which can bind to different types of HLAs on trophoblasts, suggesting that decidual NK cells play an important role in the regulation of the biological behavior of trophoblasts.[10]

During murine pregnancy, uterine NK (uNK) cells also make up the most majority of the maternal leukocytes, constituting nearly 70% of the lymphocyte fraction. Murine uNK were usually divided into CD3 NK1.1+ CD49a DX5+ conventional NK cells (cNK) and CD3 NK1.1+ CD49a + DX5 tissue-resident NK (trNK) cells.[11] Recent studies have demonstrated that trNK cell subset proliferated locally in physiological pregnancy and induced deciduomata, while there is minimal contribution from migrating cNKs to the proliferating pool of trNK cells.[12] cNK cells express NK1.1, NKp46, and Ly49 receptors and can recognize their targets via these surface receptors. They were supposed to eliminate tumor cells and resist infection during pregnancy upon direct contact without prior sensitization, which is an event known as natural cytotoxicity.[11] Furthermore, trNK cells were reported to promote the fetal growth via producing the growth factors pleiotrophin, osteoglycin, and osteopontin, to promote immune tolerance by regulating inflammatory TH17 cells, and to promote angiogenesis.[13],[14],[15]

Subsets of decidual natural killer cells

NK cells account for 50%–70% of immune cells at the maternal–fetal interface, and they play diverse roles in various events during pregnancy. Therefore, there must be heterogeneity among individual cells. In a recently published article on single-cell sequencing at the maternal–fetal interface in human, the authors found that decidual NK cells can be divided into the following three groups: dNK1, dNK2, and dNK3 cells, which all coexpress the tissue-resident markers CD49a and CD9.[16] dNK1 cells express CD39, CYP26A1, and B4GALNT1; dNK2 cells express ANXA1 and ITGB2; and dNK3 cells express CD160, KLRB1, and CD103, but not the innate lymphocyte cell marker CD127.[16] dNK1 cells highly express the inhibitory receptors KIR2DL1, KIR2DL2, and KIR2DL3 and the activating receptors KIR2DS1 and KIR2DS4, which can bind to HLA-Cs on trophoblasts. LILRB1, which has a high affinity for HLA-Gs on extravillous trophoblasts, is expressed only in dNK1 cells, and both dNK1 and dNK2 cells express the HLA-E receptors NKG2C, NKG2E, and NKG2A, suggesting that dNK1 cells might play unique roles in recognizing and interacting with extravillous trophoblasts, which specifically express HLA-G.[16] Another article divided decidual NK cells to resting NK cell and proliferating NK cell based on their expression of MKI67 and TOP2A.[17] Comparing to resting NK cell, proliferating NK cell enriched in the processes of cell cycle process, cellular component organization, and cell proliferation, while resting NK cells enriched in immune response, cytolysis, and regulation of molecular function.[17]

Gamliel et al.[18] identified a group of “memory” NK cells in the decidua. In repeated pregnancies, they identified a group of NK cells with highly expressed NKG2C and LILRB1, which are easily accessible in chromatin around the IFNG and VEGFA enhancers. After activation, these memory NK cells show a strong ability to secrete IFN-γ and vascular endothelial growth factor-α (VEGF-α). Moreover, the supernatant of activated memory NK cells can enhance the vascularization of isolated aortic rings and support the growth of JEG-3 cell (a trophoblast cell line) implanted subcutaneously in SCID-Beige mice, which imitate the function of memory NK cells in stimulating angiogenesis and promoting the growth of embryo-derived trophoblasts during pregnancy.[18] This might be one of the reasons for the improved placental development in repeated pregnancies than in first pregnancies.

Fu et al.[19] classified NK cells into the following four groups according to the expressions of CD11b and CD27: CD11b CD27, CD11b + CD27, CD11b CD27+, and CD11b + CD27+. CD11b CD27 NK cells showed an immature phenotype and a potential for further differentiation. In addition, CD11b + CD27 NK cells had a strong killing function, whereas CD11b CD27+ and CD11b + CD27+ NK cells had a high capacity to secrete cytokines. Moreover, >60% of decidual NK cells were CD11b CD27 cells, which showed a high expression of NKG2A and low expressions of NKG2C, NKG2D, CD11c, CD7, and CD2, indicating that decidual NK cells are less mature than NK cells in the peripheral blood and umbilical cord.[19]

The majority of decidual NK cells express CD49a (a tissue-resident marker). Mouse decidual NK cells can be divided into CD49a + Eomes Type I innate lymphocytes and CD49a + Eomes + trNK cells.[20] Fu et al.[14] confirmed that CD49a + Eomes + trNK cells can produce growth factors and promote placental and embryo development [Figure 1].
Figure 1: Subsets of decidual NK cells. Decidual NK cells can be divided into the following four groups: memory NK cells, regulatory NK cells, tolerant NK cells, and cytotoxic NK cells. Memory NK cells are induced in the decidua of women with repeated pregnancies, and they are NKG2ChiLILRB1+, with high IFN-γ and VEGF-α secretion. Regulatory NK cells include CD49a+Eomes+ NK cells, which can produce a large amount of cytokines and chemokines, such as pleiotrophin, osteoglycin, and osteopontin, regulate the immune condition, and promote fetal development. Tolerant NK cells represent a group of immature NK cells with developmental potential. They can differentiate into other subsets of decidual NK cells. CD27CD11b+ cytotoxic NK cells play a primary role in cytolysis, and they prevent infection during pregnancy. NK: Natural killer; IFN-γ: Interferon-gamma; VEGF-α: Vascular endothelial growth factor-α.

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  Function of Decidual Natural Killer Cells Top

Interaction with trophoblasts

Extra-chorionic trophoblasts play indispensable roles in placental and embryo development by invading into the decidual tissue and uterine spiral artery, which contributes to vascular remodeling and decidualization. Appropriate invasive ability of extra-chorionic trophoblasts is crucial with regard to pregnancy outcomes. Extra-chorionic trophoblasts are fetal-derived cells that are in direct contact with maternal cells. In addition, they closely interact with decidual stromal cells, vascular endothelial cells, and decidual immune cells. At the same time, decidual NK cells, which are the most abundant immune cells in the decidua, play an important role in regulating the biological behavior of trophoblasts.[21] Decidual NK cells express various KIRs, CD94/NKG2A receptors, and ILT2 receptors, which bind to HLA-C, HLA-E, and HLA-G in trophoblast, respectively.[22] The binding of HLA-E and NKG2A can inhibit NK cell activation and prevent trophoblasts from being killed. In addition, the binding of HLA-G and ILT2 can promote the secretion of inflammatory and angiogenic cytokines, such as interleukin-1β (IL-1β), IL-6, IL-8, and tumor necrosis factor-α (TNF-α), by decidual NK cells.[23] In fact, decidual NK cells are involved in the formation and maintenance of immune tolerance in the decidua, and they also play roles in cytotoxicity and virus clearance in pathogenic infection, both of which are closely related to the crosstalk between NK cells and trophoblasts.[24] The direct contact between trophoblast and CD49a + Eomes + NK via HLA-G and ILT2 stimulus the secretion of growth promoting factor of this NK cell subset, which further promote the fetal growth.[14] While it was also revealed that elevated NKp46 and CD107 expression, perforin release was related to trophoblast apoptosis and miscarriage in fetal/neonatal alloimmune thrombocytopenia, showing that antibody-dependent NK cell-mediated cytotoxicity of invasive trophoblasts as a pathological mechanism of miscarriage and hemorrhage in neonates.[1] What's more, HLA-Gs expressed on trophoblasts were found to promote the proinvasion and proangiogenesis functions of dNK cells, and the decreased expression of HLA-G and the attenuated regulatory function to dNK cells of trophoblast may be a possible mechanism of recurrent miscarriage.[25]

Decidual NK cells play a regulatory role in trophoblast function. Studies have shown that conditioned medium derived from decidual NK cells can regulate the migration and invasion of primary trophoblasts,[26],[27] suggesting that besides direct ligand–receptor binding, NK cells influence the behavior of trophoblasts by secreting cytokines. Decidual NK cells can secrete various cytokines and chemokines, such as IL-8, TNF-α, IFN-γ, transforming growth factor-β (TGF-β), and CXCL10, and angiogenic factors, such as VEGF-A, VEGF-C, and PGF.[28] In addition, receptors such as CXCR1 (receptor for IL-8), CXCR3 (receptor for CXCL-10), TNFR1, VEGFR-1 (receptor for VEGF-A), and VEGFR-3 (receptor for VEGF-C) have been confirmed to be expressed in extravillous trophoblasts.[28],[29],[30] In vitro experiments have shown that both IL-8 and CXCL-10 can promote the migration of primary trophoblasts and that blocking the expression of VEGFR can effectively inhibit the invasion of trophoblasts.[31] In addition, the migration ability of trophoblasts significantly decreased on treatment with conditioned medium derived from decidual NK cells whose VEGF secretory ability was downregulated when compared with controls, suggesting that the secretion of VEGF by decidual NK cells plays an important role in the regulation of the migration and invasion of trophoblasts.[32] On the contrary, TNFs and IFN-γ can inhibit the migration and invasion of trophoblasts by increasing the expression of PAI and the rate of proteolysis mediated by matrix metalloproteinases (MMPs).[33],[34] Thus, decidual NK cells can promote or restrict the migration and invasion of trophoblasts by secreting cytokines and chemokines and can further regulate the depth of trophoblast invasion and the extent of trophoblast-mediated spiral artery remodeling, which are of great significance to placental development and pregnancy outcomes.

Effect on placental angiogenesis and vascular remodeling

Vascular remodeling of the uterus can effectively increase placental blood flow and maintain fetal growth. Vascular remodeling can be divided into two steps. The first step involves the withdrawal of vascular endothelial cells and degradation of the extracellular matrix. This step does not require trophoblasts, but various immune cells, such as decidual NK cells and macrophages, are indispensable in this process.[35],[36],[37] Decidual NK cells can secrete a variety of MMPs, such as MMP-7 and MMP-9, which mediate the degradation of the extracellular matrix.[35] In addition, conditioned medium derived from decidual NK cells can induce the rupture of vascular smooth muscle cells and degradation of the extracellular matrix, whereas inhibitors of angiopoietin 2 can effectively antagonize the effects of decidual NK cells, suggesting that these functions of decidual NK cells are related to the secretion of angiopoietin.[36] The second step of vascular remodeling involves trophoblast invasion into the local decidual artery with rapid replacement of vascular endothelial cells and some smooth muscle cells. In this process, many decidual NK cells are found near the spiral artery, suggesting that these cells play an important role in this process.[35] Deficiency of decidual NK cells can lead to decreased or impaired angiogenesis and under-invasion of trophoblasts and is associated with recurrent abortions or preeclampsia.[38],[39] An animal model showed that the formation of placental blood vessels was significantly lower in mice lacking decidual NK cells than in controls.[40]

Function of decidual natural killer cells in immunoregulation

Decidual NK cells can not only regulate the remodeling of placental blood vessels and biological behavior of trophoblasts, but also affect the immune status at the maternal–fetal interface. During embryo implantation, an appropriate proinflammatory environment is conducive to the attachment and implantation of the embryo and angiogenesis. Localizations of decidual NK cells and neutrophils have been reported to overlap significantly in early pregnancy, suggesting the presence of an interactive relationship between decidual NK cells and neutrophils.[41] Cytokines secreted by decidual NK cells (e.g., granulocyte-macrophage colony-stimulating factor and IFN-γ) can induce the activation of neutrophils, promote the expressions of CD64 and CD11b in neutrophils, and contribute to the survival of neutrophils.[42],[43],[44] Thus, decidual NK cells play an important role in the formation of an inflammatory environment in early pregnancy.

Decidual NK cells are also important for the maintenance of immune tolerance after embryo implantation. CD56bright CD27+ NK cells in the decidua have been shown to inhibit the expansion of Th17 cells and the production of IL-17 by secreting IFN-γ. Exhaustion of CD56bright CD27+ NK cells can increase the proportion of Th17 cells, concentration of IL-17, and absorption rate of embryos.[13] Women with recurrent spontaneous abortions were found to show decreased CD56bright CD27+ NK cells, which led to a limited inhibition of Th17 cell proliferation and IL-17 production, thereby affecting immune tolerance.[13] Decidual NK cells have also been shown to promote IDO activity and TGF-β secretion by monocytes through secreting IFN-γ, thus inducing the differentiation of regulatory T cells and promoting maternal–fetal immune tolerance [Figure 2].[45]
Figure 2: Function of decidual NK cells at the maternal–fetal interface. Decidual NK cells can crosstalk with extravillous trophoblasts through direct or indirect contact and promote the migration and invasion of trophoblasts. In addition, they can facilitate the replacement of vascular endothelial cells of the local decidual artery by the invaded trophoblasts. Moreover, decidual NK cells can interact with various immune cells, including Th17 cells, regulatory T cells, and neutrophils. Through the effects of various cytokines, decidual NK cells help maintain immune tolerance at the maternal–fetal interface. NK: Natural killer.

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  Conclusion Top

Overall, decidual NK cells accumulate at the maternal–fetal interface in early pregnancy, exhibit phenotypes completely different from those of NK cells in the peripheral blood, and play numerous and indispensable roles in various processes. Decidual NK cells closely interact with trophoblasts, vascular endothelial cells, and other decidual immune cells, such as Th17 cells, regulatory T cells, CD14+ monocytes, and dendritic cells, through direct contact or secretion of soluble molecules. They are also involved in implantation of the embryo, vascular remodeling of the placenta, and maintenance of immune tolerance at the maternal–fetal interface. Further studies continue to reveal the possible ligand-receptors associated with the relationship between decidual NK cells and trophoblasts, and cytokines and chemokines secreted by decidual NK cells have been shown to execute further different functions than those previously known. As the most abundant immune cells at the maternal–fetal interface, decidual NK cells are undoubtedly important for successful pregnancy and thus require further studies. These results might have profound significance for the management of pregnancy and pregnancy-related diseases.

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  [Figure 1], [Figure 2]


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