How does the female immune system adjust to pregnancy? A new study shows that the thymus, an important immune organ, plays a crucial role in this. Mediated by pregnancy hormones such as progesterone, this gland produces more regulatory T cells during pregnancy. These immune cells prevent the body from rejecting the embryo as a foreign body. They also regulate the mother’s sugar level and thus prevent gestational diabetes.
During pregnancy, the female body changes. The immune system, in particular, has to adjust to tolerating the embryo. Because it is only half genetically identical to the mother and therefore, strictly speaking, a foreign body. The thymus, an immune organ in the upper part of the chest, produces regulatory T cells (T-regs) that prevent maternal antibodies from reacting to the unborn child. Outside of pregnancy, T-regs are used to suppress autoimmune diseases by neutralizing malformed immune cells. How exactly the thymus function changes during pregnancy, however, was previously unknown.
Immune cells for pregnancy
A team led by Magdalena Paolino from the Karolinska Institute in Sweden has now dealt with this. Using mice, they found that the thymus gland increasingly forms the RANK receptor during pregnancy. “We knew that RANK was produced in the thymus, but the role of this receptor during pregnancy was unknown,” says Paolino. To find out more about the function of this docking site, the researchers bred genetically modified mice that lacked this receptor. As long as these mice were not pregnant, there were no noticeable deviations from other mice.
During pregnancy, however, the importance of the receptor became apparent: “If RANK was missing, hardly any T-regs were produced in the thymus,” says Paolino. “As a result, there were also fewer T-regs in the placenta, which led to a higher rate of miscarriages.” Stimulated by pregnancy hormones, RANK ensures that the production of regulatory T cells is boosted in normal pregnancies, which in turn help with this to maintain the pregnancy and protect the child from attacks by the maternal immune system.
Protection against gestational diabetes
As Paolini and her team showed in non-genetically modified mice, the regulatory T cells produced in the thymus not only migrate to the placenta, but are also stored in the maternal adipose tissue. Here they prevent inflammation and regulate the glucose level. Mice without RANK, which therefore lacked these T-regs, had more frequent problems with blood sugar during pregnancy and exhibited symptoms similar to human patients with gestational diabetes. If the pregnancy of the genetically modified mice was successful despite the problems, their offspring weighed significantly more at birth than the average newborn mice. Furthermore, the offspring were prone to diabetes and obesity throughout their lives.
The babies of people with gestational diabetes also tend to have increased birth weights and are more prone to health problems such as diabetes and obesity later in life. To find out whether the results on regulatory T cells could be transferred to humans, the researchers compared tissue samples from the placenta of women with and without gestational diabetes. And indeed: women with gestational diabetes had – just like the mice – a reduced number of regulatory T cells in their placenta. This indicates that the RANK receptor in the thymus also plays an important role in them.
Possible therapeutic approaches
This finding could open up new therapeutic approaches against pregnancy-related diabetes, as underlined by another experiment: If the researchers administered regulatory T cells from other pregnant mice to the mice without a RANK receptor, all symptoms improved: the glucose level normalized, and miscarriages were less common the offspring were born with normal weight. T-regs from non-pregnant mice, however, did not help. “The discovery of this new mechanism on which gestational diabetes is based will enable new therapeutic approaches for mother and child in the future,” explains co-author Alexandra Kautzky-Willer from the Medical University of Vienna.
“This research changes our understanding of the thymus and shows that it is an active, dynamic organ that is necessary for safe pregnancies,” says Paolini. “The results also open up new molecular insights into gestational diabetes, a disease that affects many women and about which little is known so far.” solved how pregnancy hormones change the thymus via RANK, but also revealed a new function: The thymus not only influences the immune system, but also regulates the metabolic health of the mother. “
Source: Magdalena Paolino (Karolinska Institute, Sweden) et al., Nature, doi: 10.1038 / s41586-020-03071-0