Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China.
Am J Reprod Immunol. 2022 Sep;88(3):e13562. doi: 10.1111/aji.13562. Epub 2022 May 30.
Recurrent pregnancy loss (RPL) is one of the big challenges of normal pregnancy. Immune dysregulation has been proposed for the key underline mechanisms of RPL. However, the essential roles of T cells, especially γδ T cells, have not been defined.
Decidua were obtained from normal pregnancy women or recurrent pregnancy loss patients and the surface molecules of γδ T cells in decidua were evaluated via flow cytometric analysis. The expression of PD-1 in clinical samples was analyzed by immunohistochemistry assay. The intracellular cytokines of decidual PD-1 and PD-1 γδ T cells were evaluated by flow cytometric analysis. The cytotoxicity of PD-1 γδ T cells were confirmed via an in vitro co-culture experiment. The specific inhibitors for Erk, p38 and JNK against the MAPK pathway were added to the co-culture media to evaluate the functions of the Erk, p38 and JNK.
We demonstrated that PD-1 was significantly decreased on decidual tissue γδ T cells of patients with RPL, resulting in the enhanced cytotoxicity of γδ T cells against trophoblasts. We further elucidated an Erk-dependent TNF-α production mediates the γδ T cell cytotoxicity against the trophoblast cells. Finally, the reduced expression of PD-L1 in the villi tissues of patients with RPL might be the cause of the reduction of PD-1 on the tissue γδ T cells.
Our study uncovers an important role of PD-1 expression on decidual γδ T cells in maintaining the normal pregnancy, and may provide a new strategy for immune therapy against RPL.
复发性流产（RPL）是正常妊娠面临的重大挑战之一。免疫失调被认为是 RPL 的关键潜在机制。然而，T 细胞的基本作用，尤其是γδ T 细胞的作用尚未确定。
从正常妊娠妇女或复发性流产患者中获取蜕膜组织，并通过流式细胞术分析评估蜕膜中γδ T 细胞的表面分子。通过免疫组织化学分析来分析临床样本中 PD-1 的表达。通过流式细胞术分析来评估 PD-1 在蜕膜中的表达及其对 γδ T 细胞细胞内细胞因子的影响。通过体外共培养实验来确认 PD-1γδ T 细胞的细胞毒性。将针对 MAPK 通路的 Erk、p38 和 JNK 的特定抑制剂添加到共培养培养基中，以评估 Erk、p38 和 JNK 的功能。
我们证明，RPL 患者的蜕膜组织γδ T 细胞上的 PD-1 显著减少，导致 γδ T 细胞对滋养层的细胞毒性增强。我们进一步阐明了 Erk 依赖性 TNF-α 产生介导了 γδ T 细胞对滋养层细胞的细胞毒性。最后，RPL 患者绒毛组织中 PD-L1 的表达减少可能是 PD-1 在组织γδ T 细胞上表达减少的原因。
我们的研究揭示了 PD-1 在维持正常妊娠中的蜕膜 γδ T 细胞表达的重要作用，并可能为针对 RPL 的免疫治疗提供新策略。
