Successful pregnancies rely on adaptations within the mother 1 , including marked changes within the immune system 2 . It has long been known that the thymus, the central lymphoid organ, changes markedly during pregnancy 3 . However, the molecular basis and importance of this process remain largely obscure. Here we show that the osteoclast differentiation receptor RANK 4 , 5 couples female sex hormones to the rewiring of the thymus during pregnancy. Genetic deletion of Rank (also known as Tnfrsf11a ) in thymic epithelial cells results in impaired thymic involution and blunted expansion of natural regulatory T (T reg ) cells in pregnant female mice. Sex hormones, in particular progesterone, drive the development of thymic T reg cells through RANK in a manner that depends on AIRE + medullary thymic epithelial cells. The depletion of Rank in the mouse thymic epithelium results in reduced accumulation of natural T reg cells in the placenta, and an increase in the number of miscarriages. Thymic deletion of Rank also results in impaired accumulation of T reg cells in visceral adipose tissue, and is associated with enlarged adipocyte size, tissue inflammation, enhanced maternal glucose intolerance, fetal macrosomia, and a long-lasting transgenerational alteration in glucose homeostasis, which are all key hallmarks of gestational diabetes. Transplantation of T reg cells rescued fetal loss, maternal glucose intolerance and fetal macrosomia. In human pregnancies, we found that gestational diabetes also correlates with a reduced number of T reg cells in the placenta. Our findings show that RANK promotes the hormone-mediated development of thymic T reg cells during pregnancy, and expand the functional role of maternal T reg cells to the development of gestational diabetes and the transgenerational metabolic rewiring of glucose homeostasis. RANK promotes the hormone-mediated development of thymic regulatory T cells during pregnancy; loss of RANK is associated with impaired maturation of maternal regulatory T cells, leading to fetal loss and the development of gestational diabetes.

中文翻译：

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RANK 将胸腺调节性 T 细胞与妊娠期流产和妊娠糖尿病联系起来

成功怀孕取决于母亲内部的适应 1 ，包括免疫系统内部的显着变化 2 。人们早就知道胸腺，即中央淋巴器官，在怀孕期间会发生显着变化 3 。然而，这个过程的分子基础和重要性在很大程度上仍然不清楚。在这里，我们显示破骨细胞分化受体 RANK 4、5 将女性性激素与怀孕期间的胸腺重新布线结合起来。胸腺上皮细胞中 Rank（也称为 Tnfrsf11a）的遗传缺失导致胸腺退化受损和怀孕雌性小鼠中自然调节性 T (T reg) 细胞的扩增减弱。性激素，尤其是黄体酮，以依赖于 AIRE + 髓质胸腺上皮细胞的方式通过 RANK 驱动胸腺 T reg 细胞的发育。小鼠胸腺上皮中 Rank 的耗尽导致胎盘中天然 T reg 细胞的积累减少，并增加流产次数。Rank 的胸腺缺失还会导致内脏脂肪组织中 T reg 细胞的积累受损，并且与脂肪细胞体积增大、组织炎症、母体葡萄糖耐受不良增强、胎儿巨大儿和葡萄糖稳态的长期跨代改变有关，这些都是妊娠糖尿病的所有主要特征。T reg 细胞移植挽救了胎儿丢失、母体葡萄糖耐受不良和胎儿巨大儿。在人类妊娠中，我们发现妊娠糖尿病也与胎盘中 T reg 细胞数量减少有关。我们的研究结果表明，RANK 在妊娠期间促进激素介导的胸腺 T reg 细胞发育，并将母体 T reg 细胞的功能作用扩展到妊娠糖尿病的发展和葡萄糖稳态的跨代代谢重新布线。RANK 在怀孕期间促进激素介导的胸腺调节性 T 细胞发育；RANK 的丢失与母体调节性 T 细胞的成熟受损有关，导致流产和妊娠糖尿病的发展。