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Review
. 2020 Jan 30;16(6):957-969.
doi: 10.7150/ijbs.38264. eCollection 2020.

Innate Lymphoid Cells at the Maternal-Fetal Interface in Human Pregnancy

Rui-Qi Chang  1 , Wen-Jie Zhou  1 , Da-Jin Li  1   2 , Ming-Qing Li  1   2
Affiliations
Review

Innate Lymphoid Cells at the Maternal-Fetal Interface in Human Pregnancy

Rui-Qi Chang et al. Int J Biol Sci. .

Abstract

Pregnancy constitutes a major challenge to the maternal immune system, which must tolerate fetal alloantigen encoded by paternal genes. In addition to their role in inducing maternal-fetal immune tolerance, accumulating evidence indicates that decidual immune cells are involved in several processes required for a successful pregnancy, including trophoblast invasion as well as tissue and spiral artery remodeling. Innate lymphoid cells (ILCs), an important branch of the innate immune system, which has expanded rapidly in recent years, are strong actors in mucosal immunity, tissue homeostasis and metabolism regulation. With the recent identification of ILCs in the human decidua, the role of ILCs at the maternal-fetal interface raises concern. Herein, we review the presence and characterization of ILCs in the human decidua, as well as their function in normal pregnancy and pathological pregnancy, including reproductive failure, preeclampsia and others.

Keywords: innate lymphoid cell; preeclampsia.; pregnancy; reproductive failure; spiral artery remodeling; trophoblast invasion.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
The innate lymphoid cell family at the maternal-fetal interface. The upper left shows the murine maternal-fetal interface stained by hematoxylin-eosin. And the right shows the innate lymphoid cell family at the maternal-fetal interface. All innate lymphoid cells (ILCs) arise from a common lymphoid progenitor (CLP). NK cells develop from a CLP via NK cell precursors (NKP), while the rest of the ILC subsets develop from a CLP via common helper ILC precursors (ChILP). PLZF- ChILP is restricted to lymphoid tissue inducer (LTi) cells, while PLZF+ ChILP are capable of differentiating into all non-cytotoxic helper ILC subsets, except for LTi cells. T-bet, GATA3 and RORγt are required for the lineage maintenance of NK cells, as well as ILC1s, ILC2s and ILC3s. The maternal-fetal interface is the frontier of the direct contact between the embryo and mother. It is mainly composed of fetal trophoblast cells, maternal decidual stromal cells (DSCs) and decidual immune cells (DICs), including ILCs, macrophages, T cells, B cells, etc. At the maternal-fetal interface, all the ILC subsets are identified during the third trimester, while only NK cells, ILC1s and ILC3s are present in early pregnancy. The origin of dNK cells contains in situ progenitors, as well as peripherally derived HPCs and/or pNK homing cells. The migration of NK cells from the periphery to the decidua requires chemokines, including CXCL12 and MIPI-α, secreted by trophoblasts cells, and CX3CL1, CXCL10 and CXCL12 secreted by DSCs, adhesion molecules, such as L-selectin, as well as chemerin expressed in DSC and extravillous trophoblast cells. However, little is known about the origin of the rest of the ILC subsets in the human decidua. Moreover, NK cells acquire functional competence and self-tolerance by NK cell education via constant NK receptor (NKR)-MHC interactions. Id2, inhibitor of DNA binding 2; Flt3L, Flt3 ligand; GATA3, GATA-binding protein 3; PLZF, promyelocytic leukemia zincfinger protein; RORα, retinoic acid receptor-related orphan receptor-α; RORγt, retinoid-related orphan receptor γt; AHR, aryl hydrocarbon receptor; Eomes, Eomesodermin; NCR, natural cytotoxicity receptor; DSC, decidual stromal cells; NKR, natural killer receptors; VTS, villous trophoblasts; EVTs, extravillous trophoblasts.
Figure 1
Figure 1
The innate lymphoid cell family at the maternal-fetal interface. The upper left shows the murine maternal-fetal interface stained by hematoxylin-eosin. And the right shows the innate lymphoid cell family at the maternal-fetal interface. All innate lymphoid cells (ILCs) arise from a common lymphoid progenitor (CLP). NK cells develop from a CLP via NK cell precursors (NKP), while the rest of the ILC subsets develop from a CLP via common helper ILC precursors (ChILP). PLZF- ChILP is restricted to lymphoid tissue inducer (LTi) cells, while PLZF+ ChILP are capable of differentiating into all non-cytotoxic helper ILC subsets, except for LTi cells. T-bet, GATA3 and RORγt are required for the lineage maintenance of NK cells, as well as ILC1s, ILC2s and ILC3s. The maternal-fetal interface is the frontier of the direct contact between the embryo and mother. It is mainly composed of fetal trophoblast cells, maternal decidual stromal cells (DSCs) and decidual immune cells (DICs), including ILCs, macrophages, T cells, B cells, etc. At the maternal-fetal interface, all the ILC subsets are identified during the third trimester, while only NK cells, ILC1s and ILC3s are present in early pregnancy. The origin of dNK cells contains in situ progenitors, as well as peripherally derived HPCs and/or pNK homing cells. The migration of NK cells from the periphery to the decidua requires chemokines, including CXCL12 and MIPI-α, secreted by trophoblasts cells, and CX3CL1, CXCL10 and CXCL12 secreted by DSCs, adhesion molecules, such as L-selectin, as well as chemerin expressed in DSC and extravillous trophoblast cells. However, little is known about the origin of the rest of the ILC subsets in the human decidua. Moreover, NK cells acquire functional competence and self-tolerance by NK cell education via constant NK receptor (NKR)-MHC interactions. Id2, inhibitor of DNA binding 2; Flt3L, Flt3 ligand; GATA3, GATA-binding protein 3; PLZF, promyelocytic leukemia zincfinger protein; RORα, retinoic acid receptor-related orphan receptor-α; RORγt, retinoid-related orphan receptor γt; AHR, aryl hydrocarbon receptor; Eomes, Eomesodermin; NCR, natural cytotoxicity receptor; DSC, decidual stromal cells; NKR, natural killer receptors; VTS, villous trophoblasts; EVTs, extravillous trophoblasts.
Figure 2
Figure 2
The role of decidual innate lymphoid cells in trophoblast invasion. In the human decidua, natural killer (NK) cells and group 3 innate lymphoid cells (ILC3s) participate in the invasion of extravillous trophoblast cells (EVT). Decidual NK (dNK) cells play a bi-directional regulatory role in trophoblast invasion. On the one hand, dNK cells direct this process by secreting chemokines (including interleukin (IL)-8, interferon-inducible protein (IP)-10 and XCL1) and granulocyte macrophage colony-stimulating factor (GM-CSF), which increase in response to the ligation of the NK cell-activating receptors KIR2DS1 and 4. On the other hand, NK cells also inhibit EVT invasion via TGF-β secretion. For NCR+ILC3s, the production of GM-CSF promotes trophoblast migration directly, as well as by inducing the expression of heparin-binding epidermal growth factor-like growth factor (HBEGF) and IL1ra in neutrophils.
Figure 3
Figure 3
The role of decidual natural killer cells in spiral artery remodeling. In early pregnancy, decidual natural killer (NK) cells promote the process of spiral artery remodeling by inducing vascular growth via angiogenic factors, including vascular endothelial growth factor (VEGF), angiopoietin (Ang) 1 and 2, placental growth factor (PLGF) and hepatocyte growth factor (HGF), enhancing the migration and apoptosis of vascular smooth muscle cell (VSMC) layers via interferon-γ (IFN-γ) as well as facilitating the disruption of the VSMC wall via matrix metalloproteinase (MMP) 2 and 9.
Figure 4
Figure 4
Regulation of decidual natural killer cells. At the maternal-fetal interface, natural killer (NK) cells are regulated by trophoblasts, decidual stromal cells (DSCs) and hormones. NK cells acquire functional competence and self-tolerance by NK cell education via the constant interactions between NK receptors (NKR) and the MHC molecules expressed by the trophoblast cells. Moreover, trophoblasts also promote the conversion of recruited pNK to dNK cells via the galectin-9/Tim-3 pathway. The expression of CD16 on NK cells is suppressed by DSC-derived TGFβ. Additionally, DSCs are capable of inhibiting the cytotoxicity of NK cells by expressing indoleamine 2,3-dioxygenase (IDO) as well as secreting IL-33 and prostaglandin E2 (PGE2). Also, hormones and pregnancy factors produced by trophoblasts, such as human chorionic gonadotropin (hCG), progesterone and estradiol, play a role in dNK regulation. The cytotoxicity of NK cells is suppressed by progesterone via blocking degranulation and estradiol. In addition, the proliferation of dNK cells is promoted by hCG and estradiol. Tim-3, T-cell immunoglobulin domain and mucin domain-containing molecule-3; dNK, decidual natural killer; pNK, peripheral blood natural killer.
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