Decidual Natural Killer Cells: A Good Nanny at the Maternal-Fetal Interface During Early Pregnancy

Yuefang Liu, Shujun Gao, Yangjing Zhao, Hui Wang, Qiong Pan, Qixiang Shao, Yuefang Liu, Shujun Gao, Yangjing Zhao, Hui Wang, Qiong Pan, Qixiang Shao

Abstract

Decidual natural killer (dNK) cells are the tissue-resident and major subpopulation of NK cells at the maternal-fetal interface. It has been demonstrated that dNK cells play pivotal roles in pregnancy, including keeping maternal-fetal immune tolerance, promoting extravillous trophoblast (EVT) cell invasion, and driving uterine spiral artery remodeling. However, the molecular mechanisms haven't been elucidated until recent years. In this review, we systemically introduce the generation, subsets, and surface or soluble molecules of dNK cells, which are critical for maintaining the functions of dNK cells. Further, new functions of dNK cells including well-controlled cytotoxicity, immunosurveillance and immunotrophism supporting via the cell-cell interaction between dNK cells and EVT cells are mainly focused. The molecular mechanisms involved in these functions are also illustrated. Moreover, pregnancy-associated diseases caused by the dNK cells abnormalities are discussed. It will be important for future investigations about the mechanism of maintenance of pregnancy and parturition and potential clinical applications of dNK cells.

Keywords: decidual natural killer cells; early pregnancy; extravillous trophoblast cells; functional dialogue; maternal-fetal interface.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Liu, Gao, Zhao, Wang, Pan and Shao.

Figures

Figure 1
Figure 1
Overview of the ligand-receptor pairs between dNK cells and EVT cells. KIR2DL1, 2DL2 and 2DL3 are inhibitory receptors containing ITIMs, which bind with HLA-C on EVT cells. KIR2DS1 also interacts with HLA-C on EVT cells and activates downstream by combining with an ITAM–bearing adaptor DAP12. KIR2DL4, recognizing the HLA-G on EVT cells or sG from EVT cells, exhibits structural characteristics of both activating and inhibitory KIR by possessing a transmembrane R residue and a cytoplasmic ITIM. The transmembrane R binds with the adaptor protein FcϵR1 to transduce activating signals. KIR2DL4 is located in endosomes, and transferred to the surface of dNK cells when cultured with IL-2 in vitro. LILRB1 is also the HLA-G receptors containing four ITIMs in their cytoplasmic domains. NKG2 members form a heterodimer with CD94 and recognize HLA-E. NKG2A/CD94 is an inhibitory receptor owning ITIM in their cytoplasmic. While, NKG2C/E is activating receptors associated with the DAP12. Tim-3 interacts with its ligand Gal-9 on EVT cells. R, arginine; sG, soluble HLA-G; DAP12, DNAX-activating protein of 12; ITAM, Immunoreceptor tyrosine-based activation motif. ITIM, Immunoreceptor tyrosine-based inhibitory motif.
Figure 2
Figure 2
The functional dialogue between dNK cells and EVT cells at the maternal-fetal interface. HLA-G Cycle and Gal-9/Tim-3 signal inhibit/impair degranulation process and control the cytotoxicity of dNK Cells. Human dNK cells selectively transfer GNLY but not granzymes via nanotubes to EVT cells. Transferred GNLY kills intracellular bacteria without killing the EVT cells. Sialylated protein on the target cell promotes nanotube formation, while its receptor on dNK cells need further research. KIR/HLA allorecognition system (KIR2DS1-HLA-C2 and KIR2DL4-HLA-G) drives EVT cells invasion and uterine artery remodeling via synthesizing a series of soluble factors. HLA-G-LILRB1 signal activates the PI3K-AKT pathway and drives the expression of transcription factor PBX1. Furthermore, PBX1 upregulates the transcription of the GPF including PTN and OGN and promotes fetal development.

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Source: PubMed

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