Journal Article

RANK links thymic regulatory T cells to fetal loss and gestational diabetes in pregnancy

Fededa, Juan P., Pranjic, Blanka, White, Andrea J., Bock, Christoph, Rauscher, Esther, Cronin, Shane J. F., Koglgruber, Rubina, Kautzky-Willer, Alexandra, Paolino, Magdalena, Uribesalgo, Iris, Bancher-Todesca, Dagmar, Dekan, Sabine, Penz, Thomas, Holländer, Georg A., Anderson, Graham, Harreiter, Jürgen, Novatchkova, Maria, Sigl, Verena, Schuster, Michael, Penninger, Josef M., Kenner, Lukas

2021

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/31 / 14/63 / 38/91 / 631/250/1620/1840 / 64/60 / 692/699/2743/137/1926 / 82/58 / Accumulation / Adaptation / Adipocytes - pathology / Adipose tissue / AIRE Protein / Animals / Biomedical materials / Causes of / Cell Proliferation / Cytokine receptors / Deletion / Depletion / Diabetes in pregnancy / Diabetes mellitus / Diabetes, Gestational - etiology / Diabetes, Gestational - immunology / Diabetes, Gestational - metabolism / Diabetes, Gestational - pathology / Diagnosis / Epithelial cells / Epithelial Cells - immunology / Epithelium / Female / Females / Fetal death / Fetal Death - etiology / Fetus - immunology / Fetus - metabolism / Fetus - pathology / Fetuses / Gene expression / Gestational diabetes / Glucose / Glucose - metabolism / Glucose Intolerance - genetics / Glucose tolerance / Homeostasis / Hormones / Humanities and Social Sciences / Humans / Immunoregulation / Inflammation / Intolerance / Intra-Abdominal Fat - pathology / Ligands / Lymphocytes / Lymphocytes T / Male / Mice / Mice, Inbred BALB C / Mice, Inbred C57BL / multidisciplinary / Osteoclastogenesis / Physiological aspects / Placenta / Placenta - immunology / Placenta - pathology / Pregnancy / Progesterone / Receptor Activator of Nuclear Factor-kappa B - deficiency / Receptor Activator of Nuclear Factor-kappa B - genetics / Receptor Activator of Nuclear Factor-kappa B - metabolism / Rewiring / Rodents / Science / Science (multidisciplinary) / Sex hormones / T cells / T-Lymphocytes, Regulatory - cytology / T-Lymphocytes, Regulatory - immunology / Thymic involution / Thymic stromal lymphopoietin / Thymus / Thymus gland / Thymus Gland - cytology / Thymus Gland - immunology / Transcription Factors - metabolism / Transplantation