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Immune system ‘negotiations’ stop mom’s body from attacking her fetus

One of pregnancy’s most baffling aspects has been why the mother’s immune system doesn’t destroy the developing fetus, given that—much like an invading microbe—it’s chock full of foreign material. Now, researchers have captured the intricate molecular negotiations that help keep both fetus and mom safe until the baby is delivered.

“The complexity is stunning,” says Sumati Rajagopalan, an immunologist at the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, who was not involved in the work. Understanding this communication could eventually help reduce miscarriages and other complications of pregnancy, she adds.

These complications often have roots in the earliest days of pregnancy, when the embryo starts to move into the decidua, the lining of the uterus. “The maternal-fetal interface is not well understood, but is crucial for a successful pregnancy,” says Sarah Teichmann, a computational biologist at the Wellcome Sanger Institute in Cambridge, U.K.

So, she and her colleagues decided to examine the gene activity of single cells from the mother and the fetus during this period. They studied 70,000 white blood cells and cells from the placental and decidual tissues of women who terminated their pregnancies between 6 weeks and 14 weeks of gestation. Using single-cell transcriptomics technology, they assessed each cell’s gene activity, getting a readout of which proteins were present and determined what each cell was.

They identified 35 types of cells, some new and some already known, including various embryonic cells that invade the mother’s tissue and help trigger the formation of blood vessel connections between mother and fetus. The researchers also detected multiple kinds of immune cells, including several types of so-called natural killer cells, which normally destroy infected cells and tumor cells. Then, they combed existing databases of protein interactions to determine which of these cells were interacting with each other based on these protein links.

The invading embryonic cells stimulated mother cells to make some immune cells that rein in immune responses, Teichmann and her team report today in Nature. The group also realized that at least some of the mother’s natural killer cells were peacekeepers, not warriors, preventing other immune cells from attacking the fetus and producing chemicals that promoted fetal growth and blood vessel connections. These natural killer cells are controlled, in part, by certain cells in the decidua called stromal cells. “We can now see in detail how they communicate with each other,” Teichmann says. “Our results also reveal multiple layers of regulation of immunity that were not previously appreciated.”

Many more interactions remain to be explored, Rajagopalan says. To that end, Teichmann’s group has established an online database to help other researchers do just that.