The immunology of pregnancy is complex and, for many years, has been viewed according to “classical” concepts similar to those at the basis of organ transplantation. One of the classical concepts is that pregnancy is associated with immune suppression, or “immunological weakness” so to avoid rejection of the fetus—which is seen as a foreign entity. In other words, in absence of immuno suppression, the fetus could be rejected by the mother’s immune system—as her immune system would see her own fetus similarly to a foreign tissue or organ and mount an immune response against it. This view has delayed a real understanding of how the immune system behaves during pregnancy.

In the past few years, it has becoming increasingly evident that the fetal–maternal immune interactions are more complex than depicted by the “classical” concepts. Thus, pregnancy can be defined as a unique immune condition that is modulated, but not suppressed. As pointed out by Gil Mor and Ingrid Cardenas, pregnancy is the most important period for the conservation of the species and, therefore, the immune system changes to strengthen different mechanisms that protect both mother and offspring. As they discuss in the American Journal of Reproductive Immunology, “The immune system is one of the most important systems protecting the mother against the environment and preventing damage to the fetus. It is during pregnancy when the maternal immune system is characterized by a reinforced network of recognition, communication, trafficking and repair; it is able to raise the alarm, if necessary, to maintain the well-being of the mother and the fetus. On the other side is the fetus that, without any doubt, provides a developing active immune system that will modify the way the mother responds to the environment, providing the uniqueness of the immune system during pregnancy.”

Now, results from a new study (An immune clock of human pregnancy) show that, during pregnancy, the immune system changes according to a precisely timed series of events, suggesting that there is an “immune clock” of pregnancy. While previous studies used proteomic analyses, thus relying on blood proteins to characterize immune activity during pregnancy, the new study is based on the analysis of whole cells.

For the new study, the researchers analyzed blood collected from 18 women that gave birth to full-term babies, drawn at three time-points during pregnancy—and again six weeks after birth—using a combination of mass cytometry and advanced statistical modeling techniques. Their results confirmed immune features of pregnancy that were already known while, at the same time, discovering new ones. For example, the researchers confirmed that, as already known, natural killer cells and neutrophils have enhanced action during pregnancy. They also uncovered a new finding related to the activity of the STAT5 signaling pathway in CD4⁺T cells. This activity progressively increases throughout pregnancy on a precise schedule, ultimately reaching levels much higher than in non pregnant women. The STAT5 pathway is involved in the differentiation of regulatory T cells, which are known to play a major role in maintaining pregnancy.

Nima Aghaeepour, lead author of the study, said in a press release: “It’s really exciting that an immunological clock of pregnancy exists. Now that we have a reference for normal development of the immune system throughout pregnancy, we can use that as a baseline for future studies to understand when someone’s immune system is not adapting to pregnancy the way we would expect.”