Innate and Adaptive Immune Systems in Physiological and Pathological Pregnancy

Abstract

The dynamic immunological changes occurring throughout pregnancy are well-orchestrated and important for the success of the pregnancy. One of the key immune adaptations is the maternal immune tolerance towards the semi-allogeneic fetus. In this review, we provide a comprehensive overview of what is known about the innate and adaptive immunological changes in pregnancy and the role(s) of specific immune cells during physiological and pathological pregnancy. Alongside this, we provided details of remaining questions and challenges, as well as future perspectives for this growing field of research. Understanding the immunological changes that occur can inform potential strategies on treatments for the optimal health of the neonate and pregnant individual both during and after pregnancy.

Keywords: adaptive immune system; immune cells; immunological tolerance; innate immune system; maternal–fetal interaction; pathological pregnancy; physiological pregnancy; pregnancy.

Figure 1

Innate and adaptive immune cells in physiological pregnancy. Schematic representation of immune changes in relation to their localization (i.e., maternal–fetal interface = blue; maternal circulation = red) throughout pregnancy, namely from implantation (far left), placentation to labor (far right). Within the maternal circulation, overall T cells do not significantly change over gestation, but there are changes in T cell subsets; reactive T cells are decreased during pregnancy through FAS-mediated death initiated by trophoblasts, whereas the proportion of regulatory T cells (Treg) is elevated and a Th2 bias is observed. Additionally, there is a highly differentiated CD8⁺ effector memory cell sub-type present at the human decidua with unclear function as denoted by the question mark. B cells are primarily hyporesponsive and present a predominant B2 bias vs. B1 cells. At the maternal–fetal interface, neutrophils and uterine NK cells are highly involved in angiogenesis and vascular remodeling early in pregnancy. Macrophages are activated early in pregnancy, polarize from M1 to M2 mid-gestation, and are again activated in great numbers during labor. DCs interact with macrophages and decidual NK cells; they also inhibit the activation of T cells and are involved early in pregnancy during placentation. The number of neutrophils increase in infiltration of the maternal–fetal interface at the time of labor. Created with BioRender.com (accessed on 16 January 2023).

Figure 2

Innate and adaptive immune cells in pathological pregnancy. Changes related to specific cell types in the following pathological pregnancies: preterm birth (PTB), preeclampsia (PE), recurrent spontaneous abortion (RSA), villitis of unknown etiology (VUE), and intra-uterine growth restriction (IUGR). Reported changes in the maternal circulation are presented with red arrows, whereas changes at the maternal–fetal interface are in blue. Grey squares/question marks: unknown/no consensus found in the literature. PTB: Th17 cells are decreased whilst monocytes/macrophages and B cells are increased in the maternal circulation. Fetal macrophages are thought to be involved in placental inflammation. There is a pro-M1 polarization bias at the maternal–fetal interface. PE: DCs activate CD4⁺ T cells and circulating DCs are activated by GM-CSF and infiltrate the maternal–fetal interface. Although neutrophils increase in number, they have decreased phagocytic function in maternal circulation and at the maternal–fetal interface. T cells in general are increased in the maternal circulation and have increased cytotoxic potential. There is also an M1 polarization bias. RSA: NK cells have increased cytotoxicity in the maternal–fetal interface. There are increases in B cells in the maternal circulation and decreased protective IgG maternal cytotoxic antibodies. There is decreased cathepsin E production in macrophages at the decidua which are also involved in Fas-mediated apoptosis of trophoblasts. There is also a skewed M1/M2 macrophage population in the decidua; low circulating levels of monocytes is also indicative of RSA. VUE: CD8⁺ T cells increase in number and in their activation status. Both M1 and M2 macrophages are elevated with a predominance of M1. IUGR: CD8⁺ T cells increase in number and are found to be activated at the maternal–fetal interface. There is conflicting data on decreases in NK cells at the maternal–fetal interface. There is an increase in B cells in the maternal circulation. Created with BioRender.com (accessed on 16 January 2023).