RANK links thymic Tregs to fetal loss and gestational diabetes in pregnancy

MAGDALENA PAOLINO; RUBINA KOGLGRUBER; SHANE J. F. CRONIN; IRIS URIBESALGO; ESTHER RAUSCHER; JÜRGEN HARREITER; MICHAEL SCHUSTER; DAGMAR BANCHER-TODESCA; BLANKA PRANJIC; MARIA NOVATCHKOVA; JUAN PABLO FEDEDA; ANDREA J. WHITE; VERENA SIGL; SABINE DEKAN; THOMAS PENZ; CHRISTOPH BOCK; LUKAS KENNER; GEORG A. HOLLÄNDER; GRAHAM ANDERSON; ALEXANDRA KAUTZKY-WILLER; JOSEF M. PENNINGER

NATURE

NATURE PUBLISHING GROUP

Lugar: Londres; Año: 2021 vol. 589 p. 442 - 447

0028-0836

Successful pregnancies rely on adaptations within the maternal organism 1 , including marked changes within the immune system 2 . It has been long known that the thymus, the central lymphoid organ, changes dramatically during pregnancy 3 . Yet, the molecular basis and significance of this process remain largely obscure. Here we show that the osteoclast differentiation receptor RANK 4,5 couples female sex hormones to rewiring of the thymus during pregnancy. Genetic deletion of Rank in thymic epithelial cells results in impaired thymic involution and blunted expansion of natural Tregs in pregnant females. Sex hormones, in particular progesterone, drive Aire + mTEC- dependent development of thymic Tregs via RANK, and Rank deletion in the thymic epithelium results in reduced accumulation of natural Tregs in the placenta, accompanied by elevated miscarriages. Thymic deletion of Rank also resulted in impaired Treg accumulation in visceral adipose tissue, associated with enlarged adipocyte size, tissue inflammation, enhanced maternal glucose intolerance, fetal macrosomia, and long-lasting transgenerational alteration in glucose homeostasis; key hallmarks of gestational diabetes. Treg transplantation rescued fetal loss, maternal glucose intolerance and fetal macrosomia. In human pregnancies, gestational diabetes also correlates with reduced Tregs in the placenta. Our findings show that RANK promotes hormone-mediated development of thymic Tregs in pregnancy and expand the functional role of maternal Tregs to gestational diabetes and transgenerational metabolic rewiring of glucose homeostasis.