The distinct human leukocyte antigen (HLA) class I expression pattern of human extravillous trophoblasts (EVT) endows them with unique tolerogenic properties that enable successful pregnancy. Nevertheless, how this process is elaborately regulated remains elusive. Previously, E74 like ETS transcription factor 3 (ELF3) was identified to govern high-level HLA-C expression in EVT. In the present study, ELF3 is found to bind to the enhancer region of two adjacent NOD-like receptor (NLR) genes, NLR family pyrin domain-containing 2 and 7 (NLRP2, NLRP7). Notably, our analysis of ELF3-deficient JEG-3 cells, a human choriocarcinoma cell line widely used to study EVT biology, suggests that ELF3 transactivates NLRP7 while suppressing the expression of NLRP2. Moreover, we find that NLRP2 and NLRP7 have opposing effects on HLA-C expression, thus implicating them in immune evasion at the maternal–fetal interface. We confirmed that NLRP2 suppresses HLA-C levels and described a unique role for NLRP7 in promoting HLA-C expression in JEG-3. These results suggest that these two NLR genes, which arose via gene duplication in primates, are fine-tuned by ELF3 yet have acquired divergent functions to enable proper expression levels of HLA-C in EVT, presumably through modulating the degradation kinetics of IkBα. Targeting the ELF3–NLRP2/NLRP7–HLA-C axis may hold therapeutic potential for managing pregnancy-related disorders, such as recurrent hydatidiform moles and fetal growth restriction, and thus improve placental development and pregnancy outcomes.

中文翻译：

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绒毛外滋养细胞中 HLA-C 的表达由 ELF3–NLRP2/NLRP7 调节轴决定


人类绒毛外滋养细胞 (EVT) 独特的人类白细胞抗原 (HLA) I 类表达模式赋予它们独特的耐受性，从而能够成功妊娠。然而，如何精心监管这一过程仍然难以捉摸。此前，E74 与 ETS 转录因子 3 (ELF3) 一样被确定可控制 EVT 中的高水平 HLA-C 表达。在本研究中，发现 ELF3 与两个相邻的 NOD 样受体 (NLR) 基因的增强子区域结合，即包含 NLR 家族 Pyrin 结构域的 2 和 7 (NLRP2、NLRP7)。值得注意的是，我们对 ELF3 缺陷型 JEG-3 细胞（一种广泛用于研究 EVT 生物学的人绒毛膜癌细胞系）的分析表明，ELF3 反式激活NLRP7同时抑制NLRP2的表达。此外，我们发现 NLRP2 和 NLRP7 对 HLA-C 表达具有相反的作用，因此表明它们参与母胎界面的免疫逃避。我们证实 NLRP2 抑制 HLA-C 水平，并描述了 NLRP7 在促进 JEG-3 中 HLA-C 表达方面的独特作用。这些结果表明，这两个 NLR 基因是通过灵长类动物中的基因复制产生的，可通过 ELF3 进行微调，但已获得不同的功能，以在 EVT 中实现 HLA-C 的适当表达水平，大概是通过调节 IkBα 的降解动力学。靶向 ELF3–NLRP2/NLRP7–HLA-C 轴可能具有治疗妊娠相关疾病的潜力，例如复发性葡萄胎和胎儿生长受限，从而改善胎盘发育和妊娠结局。