RANK links thymic regulatory T cells to fetal loss and gestational diabetes in pregnancy
RANK links thymic regulatory T cells to fetal loss and gestational diabetes in pregnancy
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DOI：
10.1038/s41586-020-03071-0
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发表时间：
2020-12-23
期刊：
影响因子：
64.8
通讯作者：
Penninger, Josef M.
中科院分区：
文献类型：
--
作者：
Paolino, Magdalena;Koglgruber, Rubina;Penninger, Josef M.
成功的怀孕取决于母亲的适应能力，包括免疫系统的显著变化(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著变化(3)。然而，这一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，我们表明破骨细胞分化受体RANK(4，5)将女性性激素与怀孕期间胸腺的重新连接联系在一起。胸腺上皮细胞Rank(也称为Tnfrsf11a)的基因缺失会导致怀孕雌性小鼠胸腺退化和自然调节性T(T-reg)细胞的钝化扩张。性激素，特别是孕激素，以一种依赖于AIRE(+)髓质胸腺上皮细胞的方式，通过RANK推动胸腺T-reg细胞的发育。Rankin在小鼠胸腺上皮的耗尽导致胎盘中自然T-reg细胞的减少，并增加了流产的次数。胸腺Rank基因缺失还会导致T-reg细胞在内脏脂肪组织中的聚集受损，并与脂肪细胞体积增大、组织炎症、母亲糖耐量增加、巨大儿以及长期跨代改变血糖稳态有关，这些都是妊娠期糖尿病的关键特征。T-reg细胞移植挽救了胎儿丢失、母亲糖耐量异常和巨大儿。在人类怀孕期间，我们发现妊娠期糖尿病也与胎盘中T-reg细胞数量的减少有关。我们的研究结果表明，RANK促进了妊娠期间胸腺T-reg细胞由激素介导的发育，并扩大了母体T-reg细胞在妊娠期糖尿病的发生和葡萄糖代谢平衡跨代代谢重排中的作用。
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 Rankin 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.