Pregnancy represents a unique state of immunological tolerance between the mother and the developing conceptus (1, 2). The maternal immune system undergoes drastic changes to prevent an unwanted semiallogeneic response against the fetus while still responding to invading pathogens in a tightly regulated manner (3). The fetal immune system also establishes tolerance toward maternal Ags (4). Thus, we highlight the cooperative effort of “Maternal–Fetal Immunology” in this third special issue of The Journal of Immunology featuring a small collection of Brief Reviews (5–9).
The first two reviews, by Colucci (5) and Moldenhauer et al. (6), discuss new advances in our understanding of the cellular mechanisms of NK cells and regulatory T cells (Tregs) during pregnancy. Next, Collins, McCutcheon, and Petroff (7) summarize how female sex hormones (estrogen and progesterone) influence barrier functions and cellular immunity in the reproductive tract. Then, Miller et al. (8) highlight recent investigations that use single-cell technologies to reveal new cellular processes and interactions at the maternal–fetal interface. Lastly, Shook, Fourman, and Edlow (9) provide a timely assessment of current knowledge regarding the immune response induced by coronavirus disease 2019 (COVID-19) in the mother, the placenta, and the fetus, and they draw on experience from previous pandemics to identify the likely long-term adverse effects of prenatal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the offspring. Together, the five outstanding contributions to this Special Issue provide a timely update on maternal–fetal immunology and highlight specific gaps in knowledge that require continued investigation.
In the first entry of this collection, Colucci (5) argues for the importance of reproductive fitness in driving the evolution of NK cell education during pregnancy. Reproduction represents a unique scenario in which NK cells at the maternal–fetal interface must be educated to tolerate the invasive trophoblast, and the key signaling pathways implicated in this process are an area of ongoing investigation. Notably, Colucci (5) emphasizes that NK cell education at the maternal–fetal interface differs from that of peripheral NK cells, and that such education likely relies on interactions with multiple cell types, including the stromal and myeloid cells present in the decidua. Based on current evidence, the interactions between CD94:NKG2A and specific nonclassical HLAs are proposed as genetic determinants of NK cell education.
The molecular mechanisms underlying the control of Treg function and dysfunction during pregnancy and its complications represent an important area of investigation. Moldenhauer et al. (6) explore an emerging area of research focused on the role of metabolic factors in regulating the Tregs that are essential for maternal–fetal tolerance. Different metabolic pathways are known to exert specific influences on T cell commitment and immune function: while induction of the glycolytic pathway is critical for Th1 and Th17 cells, Tregs are more reliant on fatty acid oxidation and oxidative phosphorylation, and thus disruption of these processes can influence their function. During pregnancy, an observed decline in glycolysis may contribute to constrained effector T cell responses. By contrast, pregnant women who experience hyperinsulinemia show impairment of this shift. Indeed, pregnancies affected by metabolic disorders, such as gestational diabetes, are associated with Treg dysfunction. Yet, given the lack of robust clinical testing and classification for identifying patients with different immune-related disorders, the authors emphasize that the administration of appropriate personalized care remains an ongoing challenge.
Ascending microbial invasion from the lower female reproductive tract (FRT) is the most common route of intrauterine infection, and thus host immune–pathogen interactions taking place in this compartment represent a key area of interest. Collins et al. (7) discuss how female sex hormones (e.g., estrogen and progesterone) could affect barrier functions and cellular immunity in this compartment. Hormonally regulated changes are observed in the viscosity of cervicovaginal mucus, as well as in the composition of the antimicrobial peptides and other mediators present in this fluid. The authors systematically present evidence for hormonal regulation of individual innate and adaptive immune cell subsets by incorporating studies of the periphery and the FRT. Importantly, hormone-driven changes could alter susceptibility to specific infections during pregnancy, and thus future investigations of host immune–pathogen interactions in the FRT should consider the role of steroid hormones in such immune modulation.
As we are reminded in the earlier reviews, the establishment and maintenance of pregnancy relies on a complex network of cellular interactions within the different compartments of the maternal–fetal interface. The emergence of single-cell technologies has provided new tools that can be leveraged to investigate such dynamic cellular networks implicated in the physiological process of labor and the disease mechanisms of obstetrical complications. Miller et al. (8) provide an overview of knowledge that has been generated through single-cell approaches targeting the maternal–fetal interface during normal pregnancy, in physiological parturition, and in obstetrical disease such as preterm labor and preeclampsia. This review highlights the translational applications of single-cell signatures derived from the maternal–fetal interface, which have been integrated with the maternal peripheral blood transcriptome to enable their potential as biomarkers to monitor pregnancy and predict disease. Thus, single-cell technology represents a powerful tool for revealing novel cellular pathways and interactions with translational relevance for obstetrical disease.
The current COVID-19 pandemic instigated a massive redirection of scientific resources to uncover the impact of SARS-CoV-2 on pregnant individuals and their fetuses, yet the effects of COVID-19 on the long-term development of offspring are still poorly understood. Shook et al. (9) summarize current knowledge of the maternal, fetal, and placental immune responses induced by SARS-CoV-2 infection and then leverage observations from other disease contexts to further extrapolate on potential consequences of COVID-19 in pregnancy. Among the known long-term effects of maternal immune activation is cardiometabolic disease observed in animal models, and epidemiological evidence of influenza pandemics supports a similar predisposition in the offspring of infected mothers. Preliminary data from the COVID-19 pandemic have also pointed to neurodevelopmental alterations as evidenced by developmental delays in a subset of such offspring. The authors emphasize the current lack of data and the need for longitudinal follow-up studies to further understand the adverse effects of maternal COVID-19 on the offspring, which can help identify the best management strategies.
The reviews collected in this issue provide novel insights into different aspects of maternal–fetal immunology, together with their translational relevance for reproductive health and obstetrical complications. The improved understanding of how maternal and fetal immunity are regulated is essential to promote the development of predictive models and biomarkers, as well as targeted treatments that can promote successful pregnancy and ensure the short- and long-term health of the offspring.
Section Editor, The Journal of Immunology