The single-cell immune profile throughout gestation and its potential value for identifying women at risk for spontaneous preterm birth

Abstract

Precisely timed immune adaptations, observed in the maternal circulation, underpin the notion of an immune clock of human pregnancy that supports its successful progression and completion at delivery. This immune clock is divided into three immunological phases, with the first phase starting at the time of conception and implantation, shifting into the second phase that supports homeostasis and tolerance throughout pregnancy, and culminating in the last phase of labor and parturition. Disruptions of this immune clock are reported in pregnancy complications such as spontaneous preterm birth. However, our understanding of the immune clock preceding spontaneous preterm birth remains scattered. In this review, we describe the chronology of maternal immune cell adaptations during healthy pregnancies and highlight its disruption in spontaneous preterm birth. With a focus on single-cell cytometric, proteomic and transcriptomic approaches, we review recent studies of term and spontaneous preterm pregnancies and discuss the need for future prospective studies aimed at tracking pregnancies longitudinally on a multi-omic scale. Such studies will be critical in determining whether spontaneous preterm pregnancies progress at an accelerated pace or follow a preterm-intrinsic pattern when compared to those delivered at term.

Keywords: Immune clock of pregnancy; Immune response; Maternal immune adaptation; Single-cell proteome and transcriptome; Spontaneous preterm labor and birth.

Fig. 1

The immune clock of human pregnancy in uncomplicated and spontaneous preterm birth pregnancies. Solid lines reflect immune dynamics observed in uncomplicated pregnancy, while bold text in red and dotted lines indicate observations made in pregnancies affected by spontaneous preterm birth. Scarcity of studies on single-cell immune profiles throughout preterm pregnancies, as displayed in this overview, currently limit the opportunity to leverage these dynamics for sPTB prediction. ILC: innate lymphoid cell, Breg: regulatory B cell, WBC: white blood cell, NLR: neutrophil-to-lymphocyte ratio, NΦ: neutrophil, MΦ: macrophage, MC: monocyte, intMC: intermediate monocyte, Treg: CD4⁺regulatory T cell, Teff: T effector cell, NK: Natural Killer cell, MFI: maternal-fetal interface, PBMC: peripheral blood mononuclear cell, IL: interleukin.