Dataset Information

Polarization disorder of decidual NK cells in unexplained recurrent spontaneous abortion revealed by single-cell transcriptome analysis.

ABSTRACT:

Background

Unexplained recurrent spontaneous abortion (URSA) is one of the most common diseases in pregnancy and is mainly caused by immune disorders. The foetus is similar to semiallogeneic maternal tissue, so the balance of immune tolerance must be dynamically maintained during pregnancy. Decidual natural killer (dNK) cells primarily mediate the immune tolerance microenvironment at the maternal-fetal interface. By using single-cell RNA sequencing (scRNA-seq) and high-throughput transcriptome sequencing analysis, we explored the characteristic distribution of dNK cells in URSA patients.

Methods

Control maternal-fetal interface tissue (from normal pregnant women, n = 3) and case maternal-fetal interface tissue (from patients with URSA, n = 3) samples were analysed by scRNA-seq and high-throughput transcriptome sequencing.

Results

By scRNA-seq, we demonstrated the maturation process of the transition of dNK cells from cytotoxic characteristics to immune tolerance in transcriptome analysis. Moreover, compared with normal pregnant women, serious disturbances in the polarization process of dNK cells were found in URSA. Simultaneously, the transcriptional level of the extracellular matrix (ECM) in URSA patients showed a significant decrease. The dNK cells interacted with extravillous trophoblasts to achieve immune-tolerant polarization.

Conclusions

Insufficient expression of KIRs during dNK cell differentiation might be a key reason why polarized dNK cells still had high cytotoxic reactivity in URSA patients. Abnormal expression of ECM may affect the interaction of dNK cells with EVTs, making dNK cells immature. Both resulted in maternal immune intolerance to the foetus during pregnancy.

SUBMITTER: Pan D

PROVIDER: S-EPMC9327377 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Deficiency in decidualization has been widely regarded as an important cause of spontaneous abortion. Generalized decidualization also includes massive infiltration and enrichment of NK cells. However, the underlying mechanism of decidual NK (dNK) cell residence remains largely unknown. Here, we observe that the increased macroautophagy/autophagy of decidual stromal cells (DSCs) during decidualization, facilitates the adhesion and retention of dNK cells during normal pregnancy. Mechanistically, this process is mediated through activation of the MITF-TNFRSF14/HVEM signaling, and further upregulation of multiple adhesion adhesions (e.g. Selectins and ICAMs) in a MMP9-dependent manner. Patients with unexplained spontaneous abortion display insufficient DSC autophagy and dNK cell residence. In addition, poor vascular remodeling of placenta, low implantation number and high ratio of embryo loss are observed in NK cell depletion mice. In therapeutic studies, low doses of rapamycin, a known autophagy inducer that significantly promotes endometrium autophagy and NK cell residence, and improves embryo absorption in spontaneous abortion mice models, which should be dependent on the activation of MITF-TNFRSF14/HVEM-MMP9-adhension molecules axis. This observation reveals novel molecular mechanisms underlying DSCs autophagy-driven dNK cell residence, and provides a potential therapeutic strategy to prevent spontaneous abortion.Abbreviations: ACTA2/αSMA: actin alpha 2, smooth muscle; ATG: autophagy-related; ATG5over ESC: ATG5-overexpressed ESCs; BTLA: B and T lymphocyte associated; CDH1: cadherin 1; CDH5: cadherin 5; CXCL12: C-X-C motif chemokine ligand 12; dNK: decidual NK; DIC: decidual immune cell; DSC: decidual stromal cell; EOMES: eomesodermin; ESC: endometrial stromal cell; FCGR3A/CD16: Fc fragment of IgG receptor IIIa; HUVEC: human umbilical vein endothelial cell; ICAM: intercellular cell adhesion molecule; ILC: innate lymphoid cell; ITGB1: integrin subunit beta 1; ITGA2: integrin subunit alpha 2; IPA: Ingenuity Pathway Analysis; KIR2DL1: killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1; KLRD1/CD94: killer cell lectin like receptor D1; KLRK1/NKG2D: killer cell lectin like receptor K1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; 3-MA: 3-methyladenine; MITF: melanocyte inducing transcription factor; MiT-TFE: microphthalmia family of bHLH-LZ transcription factors; MMP9: matrix metalloproteinase 9; MTOR: mechanistic target of rapamycin kinase; NCAM1/CD56: neural cell adhesion molecule 1; NCR2/NKp44: natural cytotoxicity triggering receptor 2; NK: natural killer; KLRB1/NK1.1: killer cell lectin like receptor B1; NP: normal pregnancy; PBMC: peripheral blood mononuclear cell; PECAM1/CD31: platelet and endothelial cell adhesion molecule 1; pNK: peripheral blood NK; PRF1/Perforin: Perforin 1; PTPRC/CD45: protein tyrosine phosphatase receptor type C; Rapa: rapamycin; rh-TNFSF14/LIGHT: recombinant human TNFSF14/LIGHT; SA: spontaneous abortion; SELE: selectin E; SELP: selectin P; SELL: selectin L; siATG5 DSCs: ATG5-silenced DSCs; siTNFRSF14/HVEM DSCs: TNFRSF14/HVEM-silenced DSCs; TBX21/T-bet: T-box transcription factor 21; SQSTM1/p62: sequestosome 1; TNFRSF14/HVEM: TNF receptor superfamily member 14; TNFSF14/LIGHT: TNF superfamily member 14; uNK: uterine NK; UIC: uterine immune cell; USC: uterine stromal cell; VCAM1: vascular cell adhesion molecule 1; VIM: vimentin.