Department of Metabolism, Digestion and Reproduction, Institute of Developmental Reproductive and Developmental Biology, Imperial College London, London, United Kingdom.
The Fertility Centre, Chelsea and Westminster Hospital, London, United Kingdom.
Front Immunol. 2023 Jan 13;13:1108163. doi: 10.3389/fimmu.2022.1108163. eCollection 2022.
A significant proportion of recurrent miscarriage, recurrent implantation failure and infertility are unexplained, and these conditions have been proposed to have an etiology of immunological dysfunction at the maternal-fetal interface. Uterine Natural Killer cells (uNK) comprise three subsets and are the most numerous immune cells found in the uterine mucosa at the time of implantation. They are thought to play an important role in successful pregnancy by regulation of extravillous trophoblast (EVT) invasion and spiral artery remodelling. Here, we examine the frequency, phenotype and function of uNK1-3 from the uterine mucosa of 16 women with unexplained reproductive failure compared to 11 controls with no reproductive problems, during the window of implantation. We report that KIR2DL1/S1 and LILRB1 expression is lower in the reproductive failure group for both uNK (total uNK, uNK 2 and 3) and pNK. We also show that degranulation activity is significantly reduced in total uNK, and that TNF-α production is lower in all uNK subsets in the reproductive failure group. Taken together, our findings suggest that reproductive failure is associated with global reduction in expression of uNK receptors important for interaction with HLA-C and HLA-G on EVT during early pregnancy, leading to reduced uNK activation. This is the first study to examine uNK subsets during the window of implantation in women with reproductive failure and will serve as a platform to focus on particular aspects of phenotype and function of uNK subsets in future studies. Further understanding of uNK dysregulation is important to establish potential diagnostic and therapeutic targets in the population of women with unexplained reproductive failure.
相当一部分复发性流产、反复着床失败和不孕的原因不明，这些情况被认为与母体-胎儿界面的免疫功能障碍有关。子宫自然杀伤细胞（uNK）分为三个亚群，是着床时子宫黏膜中数量最多的免疫细胞。它们通过调节绒毛外滋养细胞（EVT）浸润和螺旋动脉重塑，被认为在成功妊娠中发挥重要作用。在这里，我们研究了 16 名不明原因生殖失败女性与 11 名无生殖问题对照女性在着床窗口期的子宫黏膜中 uNK1-3 的频率、表型和功能。我们报告称，在生殖失败组中，KIR2DL1/S1 和 LILRB1 的表达在 uNK（总 uNK、uNK2 和 uNK3）和 pNK 中均较低。我们还表明，总 uNK 的脱颗粒活性显著降低，所有 uNK 亚群的 TNF-α 产生在生殖失败组中均较低。综上所述，我们的研究结果表明，生殖失败与妊娠早期 EVT 上 HLA-C 和 HLA-G 相互作用的 uNK 受体表达减少有关，导致 uNK 激活减少。这是首次在生殖失败女性着床窗口期研究 uNK 亚群的研究，将为未来研究中关注 uNK 亚群表型和功能的特定方面提供平台。进一步了解 uNK 失调对于确定不明原因生殖失败女性的潜在诊断和治疗靶点非常重要。
