The key to healthy pregnancies lies in the thymus

How the immune system adapts to pregnancy has puzzled scientists for decades. Now an international team of researchers has discovered that important changes in the thymus occur in order to prevent miscarriages and gestational diabetes, publishing their results in the journal Nature.

The scientists found that female sex hormones instruct the thymus, a central organ of the immune system, to produce specialised cells called ‘Tregs’ to deal with physiological changes to arise during pregnancy. They also found that RANK, a receptor expressed in a part of the thymus called the epithelium, is the key molecule behind this mechanism.

“We knew RANK was expressed in the thymus, but its role in pregnancy was unknown,” said senior author Dr Josef Penninger, founding director of the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), who is now director of the Life Sciences Institute of The University of British Columbia. To gain deeper insights, 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. That resulted in less Tregs in the placentas, leading to elevated rates of miscarriage,” said lead author Magdalena Paolino, a former postdoctoral fellow at IMBA, who now heads her own laboratory at the Karolinska Institutet.

The findings also offer new molecular insights into the development of gestational diabetes, a disease that affects approximately 15% of pregnant women worldwide and yet puzzles scientists to this day. In healthy pregnancies, the researchers found that Tregs migrated 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 larger-than-average young.

“Similar to babies of women with gestational diabetes, the newborn pups were much heavier than average,” Paolino said.

The deficiency of Tregs during pregnancy in mothers also resulted in long-lasting transgenerational effects on the offspring, which remained prone to diabetes and overweight throughout their life spans. Interestingly, administering thymus-derived Tregs isolated from normal pregnancies to the RANK-deficient mice reversed all the mice’s health issues, including miscarriage and maternal glucose levels, and also normalised the body weights of the pups.

The researchers also analysed women with gestational diabetes, revealing a reduced number of Tregs in their placentas, similar to the study on mice. According to co-author Dr Alexandra Kautzky-Willer, from the Medical University of Vienna, “The discovery of this new mechanism underlying gestational diabetes potentially offers new therapeutic targets for mother and foetus in the future.”

Dr Penninger concluded, “The thymus changes massively during pregnancy, and how such rewiring of an entire tissue contributes to a healthy pregnancy has been one of the remaining mysteries of immunology. Our work over many years has now not only solved this puzzle — pregnancy hormones rewire the thymus via RANK — but uncovered a new paradigm for its function: the thymus not only changes the immune system of the mother so it does not reject the foetus, but the thymus also controls metabolic health of the mother.

“This research changes our view of the thymus as an active and dynamic organ required to safeguard pregnancies.”

Image credit: ©IMBA/Kulcsar

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