Scientists from the University of British Columbia (UBC) have for the first time described the role of the thymus organ, a small immune system gland that is often forgotten and is tucked behind the breastbone (sternum), in healthy pregnancies.
The study, published in the journal Nature, highlights the importance of the organ in regulating immunity and metabolic control, which in turn helps prevent miscarriages and diabetes in pregnant people.
It has been a longstanding question of how the immune system adapts during pregnancy to support mother and fetus, so researchers from UBC decided to tackle it by assessing what role the thymus might have in this process in mice animal models.
Investigating the question, the researchers discovered that female sex hormones circulating during pregnancy have an important effect on the thymus, instructing the organ to produce specialized cells called regulatory T cells, also known as Tregs. These cells help regulate some of the physiological changes that take place during pregnancy and are required for a healthy pregnancy.
Furthermore, the researchers uncovered that specialized receptors commonly expressed in cells of the thymus called RANK receptors have an important role in regulating the production of these specialized Treg cells.
“We knew RANK was expressed in the thymus, but its role in pregnancy was unknown,” said senior study author Professor Josef Penninger in a press release.
Through genetic modification, the researchers depleted RANK receptors from the animals’ thymus during their investigation. "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 Dr Magdalena Paolino.
The Tregs also seem to be important for metabolic regulation during pregnancy. The authors of the study described how these cells migrated to fat tissue in the pregnant mice to help prevent inflammation and to help regulate glucose and insulin levels. Animals lacking the RANK receptor had elevated glucose and insulin in their blood, including other indicators of gestational diabetes. The researchers also noted that the pups born from these animals were on average larger in body weight than pups born from normal pregnancies.
To confirm that Tregs were the important player in these observable changes, the researchers gave animals that were depleted of the RANK receptors thymus-derived Tregs isolated from other normal pregnancies. All of the observed changes were completely reversible by providing Tregs to animals that were not able to produce these cells during pregnancy due to the lack of RANK receptors in the thymus.
"The discovery of this new mechanism underlying gestational diabetes potentially offers new therapeutic targets for mother and fetus in the future," said co-author Dr Alexandra Kautzky-Willer.
"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," added Dr Penninger. "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 fetus, 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," Penninger concluded.