How the immune system adapts to pregnancy has puzzled researchers for decades. An international team of researchers, including scientists from the IMBA – Institute for Molecular Biotechnology of the Austrian Academy of Sciences – has now discovered that important changes in the thymus occur in order to prevent miscarriages and gestational diabetes. The results are published in the journal Nature.
Female sex hormones instruct the thymus, a central organ of the immune system, to produce specialized cells called “Tregs” to deal with physiological changes that occur during pregnancy. The researchers also found that RANK, a receptor expressed in part of the thymus called the epithelium, is the key molecule behind this mechanism. The study is an international research project involving scientists from IMBA, the University of British Columbia, the Karolinska Institutet and the Medical University of Vienna.
“We knew that RANK was expressed in the thymus, but its role in pregnancy was unknown,” says the study’s lead author, Josef Penninger, IMBA group leader and founding director who is now director of the University of British Columbia’s Life Sciences Institute . To gain a deeper insight, the authors examined mice in which RANK had been removed from the thymus. “The absence of RANK prevented the production of Tregs in the thymus during pregnancy. This resulted in fewer Tregs in the placenta, which led to increased miscarriage rates,” says lead author of the study, Magdalena Paolino, a former postdoctoral fellow at IMBA who now leads since 2017 her own laboratory at the renowned Karolinska Institutet in Sweden.
The results also offer new molecular insights into the development of gestational diabetes, a disease that affects around 15 percent of women in pregnancy worldwide and which continues to confuse scientists to this day.
In healthy pregnancies, the researchers found that Tregs migrated into the mother’s adipose tissue to help prevent inflammation and help control glucose levels in the body. Pregnant mice without RANK had high levels of glucose and insulin in the blood and many other indicators of gestational diabetes, including above-average young people. “Much like babies of women with gestational diabetes, the newborn pups were much heavier than average,” says Paolino.
The lack of Tregs during pregnancy in mothers also resulted in long-lasting intergenerational effects on the offspring, who were prone to diabetes and obesity throughout their lifespan. Interestingly, administration of thymus-derived Tregs isolated from normal pregnancies to RANK-deficient mice reversed all of the mice’s health problems, including maternal miscarriages and glucose levels, and also normalized the puppy’s body weight.
The researchers also analyzed women with gestational diabetes and found a decreased number of Tregs in their placenta, similar to the study in mice. “The discovery of this new mechanism that underlies gestational diabetes may offer new therapeutic targets for the mother and fetus in the future,” says co-author Dr. Alexandra Kautzky-Willer, a clinical researcher at the Medical University of Vienna.
The thymus changes massively during pregnancy and how such rewiring of entire tissue contributes to a healthy pregnancy has been one of the remaining puzzles in immunology. Our long-term work has now not only solved this riddle – pregnancy hormones rewire the thymus via RANK – but also uncovered a new paradigm for its function: the thymus not only changes the mother’s immune system so that it does not reject the fetus, but the Thymus also controls the mother’s metabolic health. This research is changing our view of the thymus as an active and dynamic organ necessary to secure pregnancies. “
Josef Penninger, lead author of the study
The study was made possible by a close collaboration between the Institute for Molecular Biotechnology of the Austrian Academy of Sciences in Vienna, the Life Sciences Institute in Vancouver and the Karolinska Institutet. Researchers from the CeMM Institute and the Medical University of Vienna and the University of Birmingham and Oxford in the UK also participated.
IMBA Institute for Molecular Biotechnology of the Austrian Academy of Sciences
M. Paolino et al. (2020) RANK Associates Thymus Tregs with Fetal Loss and Gestational Diabetes During Pregnancy. Nature. doi.org/10.1038/s41586-020-03071-0.