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Background <p>Recurrent pregnancy loss (RPL) remains largely unexplained in a significant subset of patients, where defective immune regulation at the maternal–fetal interface is suspected. Extravillous trophoblasts (EVT) express HLA-G1, a nonclassical MHC-I molecule crucial for immune tolerance. However, the role of HLA-G1 glycosylation in modulating the decidual natural killer (dNK) cell response remains poorly understood.</p> Methods <p>We analysed transcriptomic data and placental tissues from RPL and normal pregnancy to assess glycosylation-related alterations. Biochemical enrichment, lectin binding, and flow cytometry were used to characterize HLA-G1 sialylation. Co-immunoprecipitation and site-directed mutagenesis were used to evaluate the interaction between HLA-G1 and Siglec-7. Functional assays with JAR and NK-92MI cells were used to assess the impact on EVT invasion and NK cytotoxicity.</p> Results <p>We identified Asn110-linked sialylation as a critical posttranslational modification of HLA-G1 that enables binding to Siglec-7, an inhibitory receptor highly expressed on dNK cells. This interaction is lost upon neuraminidase treatment or Asn110 mutation, which also impairs HLA-G1 surface localization and promotes lysosomal degradation. Functionally, disruption of HLA-G1 sialylation enhances NK cytotoxicity and cytokine release while reducing EVT invasiveness.</p> Conclusions <p>Our study defines a novel glycoimmune checkpoint at the maternal–fetal interface, where Asn110-dependent HLA-G1 sialylation restrains NK cell activity via Siglec-7. This mechanism, which is disrupted in RPL, expands the physiological relevance of the Siglec axis from cancer to reproductive tolerance and highlights glycosylation as a potential target for immune modulation in pregnancy complications.</p>

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Defective HLA-G1 glycosylation disrupts Siglec-7–mediated NK cell tolerance at the maternal–fetal interface in recurrent pregnancy loss

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月25日

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  • Linyu Zhang,
  • Ying Feng,
  • Yuting Zhang,
  • Xinrui Sun,
  • Shiqi Yi,
  • Kai Wang,
  • Xue Ma,
  • Qianhong Ma,
  • Fang Ma

摘要

Background

Recurrent pregnancy loss (RPL) remains largely unexplained in a significant subset of patients, where defective immune regulation at the maternal–fetal interface is suspected. Extravillous trophoblasts (EVT) express HLA-G1, a nonclassical MHC-I molecule crucial for immune tolerance. However, the role of HLA-G1 glycosylation in modulating the decidual natural killer (dNK) cell response remains poorly understood.

Methods

We analysed transcriptomic data and placental tissues from RPL and normal pregnancy to assess glycosylation-related alterations. Biochemical enrichment, lectin binding, and flow cytometry were used to characterize HLA-G1 sialylation. Co-immunoprecipitation and site-directed mutagenesis were used to evaluate the interaction between HLA-G1 and Siglec-7. Functional assays with JAR and NK-92MI cells were used to assess the impact on EVT invasion and NK cytotoxicity.

Results

We identified Asn110-linked sialylation as a critical posttranslational modification of HLA-G1 that enables binding to Siglec-7, an inhibitory receptor highly expressed on dNK cells. This interaction is lost upon neuraminidase treatment or Asn110 mutation, which also impairs HLA-G1 surface localization and promotes lysosomal degradation. Functionally, disruption of HLA-G1 sialylation enhances NK cytotoxicity and cytokine release while reducing EVT invasiveness.

Conclusions

Our study defines a novel glycoimmune checkpoint at the maternal–fetal interface, where Asn110-dependent HLA-G1 sialylation restrains NK cell activity via Siglec-7. This mechanism, which is disrupted in RPL, expands the physiological relevance of the Siglec axis from cancer to reproductive tolerance and highlights glycosylation as a potential target for immune modulation in pregnancy complications.