How the immune system adapts to pregnancies has puzzled scientists for decades. Now, findings from an international group of researchers, led by researchers at Karolinska Institutet in Sweden, reveal important changes that occur in the thymus to prevent miscarriages and gestational diabetes. The results are published in the journal Nature.
The thymus is a central organ of the immune system where specialised immune cells called T lymphocytes mature. These cells, commonly referred to as T cells, then migrate into the blood stream and tissues to help combat pathogens and cancer. An important T cell subset, known as a regulatory T cell or Treg, is also produced in the thymus. The main function of a Treg is to help regulate other immune cells.
In the study, the researchers have found that during pregnancy, the female sex hormones instruct the thymus to produce Tregs specialised in dealing with physiological changes during pregnancy. The study--which involved researchers at Karolinska Institutet, IMBA - the Institute of Molecular Biotechnology of the Austrian Academy of Sciences in Vienna and the University of British Columbia in Vancouver--further reveals that RANK, a receptor expressed in the thymus epithelia, is the key molecule behind this mechanism.
"We knew RANK was expressed in the thymus, but its role in pregnancy was unknown", says first and co-corresponding author Dr. Magdalena Paolino, assistant professor and team leader at the Department of Medicine, Solna, Karolinska Institutet.
To get a better understanding, the authors studied mice where RANK had been deleted from the thymus.
"The absence of RANK prevented the production of Tregs in the thymus during pregnancy. This resulted in less Tregs in the placentas, leading to miscarriages," continues Magdalena Paolino.
The study further shows that in normal pregnancies, the produced Tregs also migrate to the mother's fat tissue to prevent inflammation and help control glucose levels in the body. Pregnant mice lacking RANK had high levels of glucose and insulin in their blood and many other indicators of gestational diabetes, including fetal macrosomia.
"Similar to babies of women with gestational diabetes, the newborn pups were much heavier than average," explains Magdalena Paolino.
In addition, the deficiency of Tregs during pregnancy was proven to result in long-lasting transgenerational effects on the offspring, which remained prone to diabetes and overweight throughout their life spans. Giving the RANK deficient mice thymus-derived Tregs that had been isolated from normal pregnancies, reversed all issues including fetal loss and maternal glucose levels and the body weights of the pups.
The researchers also analysed women with gestational diabetes, revealing a reduced number of Tregs in their placentas, much similar to the study on mice.
"This research changes our view of the thymus, as an active and dynamic organ required to safeguard pregnancies," Magdalena Paolino says. "It also provides new molecular insight for gestational diabetes, a disease that affects many women and which we still know little about. It emphasises the importance of clinics detecting and managing glucose metabolism in pregnant women to avert its long-term effects."
Co-corresponding author Dr. Josef Penninger notes that how rewiring of the thymus contributes to a healthy pregnancy was one of the remaining mysteries of immunology - until now.
"Our work over many years has now not only solved this puzzle - pregnancy hormones rewire the thymus via RANK - but uncovered a new paradigmatic function: the thymus not only changes the immune system of the mother to allow the fetus, but it also controls metabolic health of the mother," Josef Penninger says.
The study was possible thanks to a close collaboration between the laboratory of Magdalena Paolino at Karolinska Institutet and the laboratories of Josef Penninger at IMBA and UBC. Researchers from the CeMM Institute and the Medical University of Vienna, as well as from the University of Birmingham and Oxford in the U.K. also participated.
The researchers were supported by grants from Karolinska Institutet, the Ragnar Soderberg Foundation, the Swedish Research Council, the Swiss National Foundation, The Wellcome Trust, MRC, CRUK, Austrian Science Fund, European Training Network, IMBA, a Canada150 Chair, the T. von Zastrow foundation and the European Research Council.
Publication: "RANK links thymic Tregs to fetal loss and gestational diabetes in pregnancy", Magdalena Paolino, Rubina Koglgruber, Shane J. F. Cronin, Iris Uribesalgo, Esther Rauscher, Juergen Harreiter, Michael Schuster, Dagmar Bancher-Todesca, Blanka Pranjic, Maria Novatchkova, Andrea White, Verena Sigl, Sabine Dekan, Juan P. Fededa, Thomas Penz, Christoph Bock, Lukas Kenner, Georg A. Holländer, Graham Anderson, Alexandra Kautzky-Willer, and Josef M. Penninger, Nature, online December 23, 2020, DOI: 10.1038/s41586-020-03071-0