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Woman resting her hands on her pregnant stomach, with the sun cresting from behind her bump.
Researchers found that during pregnancy, the female sex hormones instruct the thymus to produce Tregs specialised in dealing with physiological changes during pregnancy.

How the immune system adapts to pregnancies has puzzled scientists for decades. Now, findings from an international group of researchers, led by experts at Karolinska Institutet in Sweden, reveal important changes that occur in the thymus to prevent miscarriages and gestational diabetes. The study was published today (23 December 2020) in 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.

Researchers 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, the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) in Vienna, University of British Columbia in Vancouver, further reveals that RANK, a receptor expressed in the thymus epithelia, is the key molecule behind this mechanism.

The study builds on work by a team at the University of Birmingham as researcher and collaborator Professor Graham Anderson from the Institute of Immunology and Immunotherapy explains: “In 2007, our lab provided the first evidence that RANK plays a critical role in controlling thymus function in the steady state immune system. Now, this new research shows how RANK in the thymus regulates the immune system in pregnancy, which is an exciting new direction.”

“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 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 Dr Paolino.

This latest 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 Dr 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,” Dr 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,” Dr Penninger says.

The study was possible thanks to a close collaboration between the laboratory of Dr Paolino at Karolinska Institutet and the laboratories of Dr Penninger at IMBA and UBC. Researchers from the CeMM Institute and the Medical University of Vienna, as well as from the Universities of Birmingham and Oxford also participated.