RANK links thymic regulatory T cells to fetal loss and gestational diabetes in pregnancy.
Paolino, M., Koglgruber, R., Cronin, S. J. F., Uribesalgo, I., Rauscher, E., Harreiter, J., Schuster, M., Bancher-Todesca, D., Pranjic, B., Novatchkova, M., Fededa, J. P., White, A. J., Sigl, V., Dekan, S., Penz, T., Bock, C., Kenner, L., Hollander, G. A., Anderson, G., Kautzky-Willer, A. and Penninger, J. M.
Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria. magdalena.paolino@ki.se.
Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden. magdalena.paolino@ki.se.
Karolinska University Hospital, Stockholm, Sweden. magdalena.paolino@ki.se.
Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria.
Gender Medicine Unit, Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
Research Center for Molecular Medicine of the Austrian Academy of Science (CeMM), Vienna, Austria.
Division of Obstetrics and Feto-Maternal Medicine, Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria.
Instituto de Investigaciones Biotecnologicas "Dr. Rodolfo A. Ugalde", IIB-UNSAM, IIBIO-CONICET, Universidad Nacional de San Martin, Buenos Aires, Argentina.
Institute for Immunology and Immunotherapy, Institute for Biomedical Research, Medical School, University of Birmingham, Birmingham, UK.
Department of Pathology, Medical University of Vienna, Vienna, Austria.
Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
Division of Experimental and Translational Pathology, Department of Pathology, Medical University Vienna, Vienna, Austria.
Center for Biomarker Research in Medicine (CBmed), Graz, Austria.
Unit for Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, Austria.
Christian Doppler Laboratory for Applied Metabolomics (CDL-AM), Medical University of Vienna, Vienna, Austria.
Paediatric Immunology, Department of Biomedicine, University of Basel and University Children's Hospital Basel, Basel, Switzerland.
Department of Paediatrics and The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.
Austrian Institute for Gender Medicine, Gars am Kamp, Austria.
Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria. josef.penninger@imba.oeaw.ac.at.
Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada. josef.penninger@imba.oeaw.ac.at.
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 (Treg) cells in pregnant female mice. Sex hormones, in particular progesterone, drive the development of thymic Treg 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 Treg cells in the placenta, and an increase in the number of miscarriages. Thymic deletion of Rank also results in impaired accumulation of Treg 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 Treg 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 Treg cells in the placenta. Our findings show that RANK promotes the hormone-mediated development of thymic Treg cells during pregnancy, and expand the functional role of maternal Treg cells to the development of gestational diabetes and the transgenerational metabolic rewiring of glucose homeostasis.
Nature 589(7842): 442-447 (2021)