Scientists have long been confused about the "immunological paradox" of pregnancy: how does the mother tolerate the fetus - a foreign object that carries some of the father’s DNA? In a paper in Nature, Vento-Tormo et al. studied the enigma. The researchers performed single-cell RNA sequencing (scRNAseq) of cells isolated from the placenta and decidua (pregnancy endometrium), as well as matching maternal blood comparisons. They identified a range of cell types characteristic of this maternal-fetal interface and concluded the existence of a large network of potential interactions between them that facilitate immunological tolerance and foster fetal growth. The author's molecular atlas provides an impressive resource to future studies of pregnancy and its complications.
Vento-Tormo collected placental, decidual and blood samples from pregnancies, and these samples were selectively terminated between 6 and 14 weeks of gestation. The author's scRNAseq analysis allowed them to distinguish between maternal and fetal-derived cells, as the latter include RNA sequences that are not found in the mother. This clearly indicated that cells from the fetus have migrated into the maternal decidua and that a small number of maternal immune cells called macrophages were located in the placenta.

The blastocyst-stage embryo plays an active role in its own destiny. Cells from the outer layer of the blastocyst (called trophoblast cells) undergo differentiation. Vento-Tormo and colleagues identified transcription factors that differentiate one type of trophoblast cell, villous cytotrophoblast (VCT) cells into either syncytiotrophoblasts or extravillous trophoblast (EVT) cells. The authors found that VCT cells express receptors that promote differentiation and are stimulated by growth factors produced by various placental cells. EVT cells invade the decidua, where they interact with the maternal leukocytes, triggering the stenosis of the parental spiral artery to reshape into a wider catheter that meets the nutritional needs of the developing fetus. The authors show that this invading EVT cell produces a signaling protein called transforming growth factorβthat facilitates the development of maternal regulatory T cells, a subset of immune cells called T cells, thereby suppressing immune responses.

The most abundant maternal immune cells in the decidua during the first trimester of pregnancy are natural killer (NK) cells. NK cells are known as killers of infected and tumor cells. They are more peaceful during pregnancy, secreting soluble proteins that promote maternal blood-vessel remodeling. Decidual NK (dNK) cells also regulate the extent to which EVT cells invade the diaphragm. Vento-Tormo identified three subpopulations of dNK cells –remarkable finding because it suggests that dNK cells have evolved into specialized cells that are very different from blood NK cells. The authors' data suggest that the immunological activity of each dNK subset depends on their ability to interact with both maternal and fetal cells in the decidua, as well as the dual outcome of promoting fetal growth and inhibiting immune attack on the fetal cells.

By mapping cellular and molecular topography for the first trimester of human pregnancy, current research illustrates how the maternal-fetal interface is a peaceful and tolerant environment in which immunological reactivity is dampened. In such an environment, the maternal and fetal cells synergistically regulate trophoblast invasion, remodel the maternal vasculature and provide adequate nutrition to the fetus. However, this immunological tolerance may be costly. For example, during pregnancy, the susceptibility of certain infections (such as cytomegalovirus, Zika virus and malaria-causing parasites) may be due to a restricted immune response. The data from Vento-Tormo and colleagues provides a powerful framework for assessing early pregnancy during such devastating infection.