Fetal and maternal immune cells exhibit tandem maturation across gestation and dysregulation in preterm birth

Immune cells are crucially important for the development and function of many organ systems including the maternal-fetal interface during pregnancy: the placenta and fetal membranes. While maternal uterine NK cells have been studied in pre-eclampsia, and fetal Hofbauer cells in early gestation, much less is known about fetal-derived adaptive immune cells in the placenta and their contributions to healthy gestation versus complications of pregnancy including preterm birth. In this study, we enriched immune cells from 32 term and preterm placentas (chorionic villi, decidua basalis, and cord blood) and conducted single cell transcriptomics to evaluate the state and putative function of innate and adaptive immunity accompanying fetal trophoblast cells. Gestational age was a major driver of pro-labor pro-inflammatory cytokines IL1B and TNF that in some cases were elevated too early by preterm complications. Similarly, term placentas exhibited notable expansion of TCR clones, which were gestational age-dependent except in pathologies like chorioamnionitis and vasa previa. We used genome-wide SNP calling to deconvolute the origin of fetal cells and maternal cells, finding that both mother and fetus contribute substantially to all major immune cell lineages within the placental villi. Comparing these cells to one another, we report novel candidate markers specific to fetal-derived T cells and strong expression of IL1RL1 by fetal mesenchymal cells from preterm birth cases. This work adds to our knowledge of fetal immune development and seeks to identify what immunological steps go awry in preterm birth, paving the way towards risk evaluation in pregnant mothers and ultimately preventive care.