Regulatory T Cells Play a Role in a Subset of Idiopathic Preterm Labor/Birth and Adverse Neonatal Outcomes

Abstract

SUMMARY Regulatory T cells (Tregs) have been exhaustively investigated during early pregnancy; however, their role later in gestation is poorly understood. Herein, we report that functional Tregs are reduced at the maternal-fetal interface in a subset of women with idiopathic preterm labor/birth, which is accompanied by a concomitant increase in Tc17 cells. In mice, depletion of functional Tregs during late gestation induces preterm birth and adverse neonatal outcomes, which are rescued by the adoptive transfer of such cells. Treg depletion does not alter obstetrical parameters in the mother, yet it increases susceptibility to endotoxin-induced preterm birth. The mechanisms whereby depletion of Tregs induces adverse perinatal outcomes involve tissue-specific immune responses and mild systemic maternal inflammation, together with dysregulation of developmental and cellular processes in the placenta, in the absence of intra-amniotic inflammation. These findings provide mechanistic evidence supporting a role for Tregs in the pathophysiology of idiopathic preterm labor/birth and adverse neonatal outcomes.

A Protocol for Evaluating Vital Signs and Maternal-Fetal Parameters Using High-Resolution Ultrasound in Pregnant Mice

“…In our studies, we have observed normal body temperature readings that fall within a range of 36°C–37°C, as observed in Methods Video S1 . For blood pressure, we have observed the following ranges in the control pregnant mice: systolic (144.9±14.4 mmHg), diastolic (98.7±14.2 mmHg), and mean (113.7±13.3 mmHg) ( Gomez-Lopez et al., 2020 ), as shown in Figure 4 C. The maternal heart rate has been typically observed to be between 400–500 bpm in our studies, and a representative maternal heartbeat is demonstrated in Methods Video S5 . We previously reported a mean fetal heart rate of 188.3±27.9 bpm ( Gomez-Lopez et al., 2020 ), and a representative fetal heartbeat is demonstrated in Methods Video S6 .…”

“…Moreover, Treg-depleted mice did not undergo changes in body temperature, mean blood pressure, or maternal heart rate. The uterine artery pulsatility index decreased in mice with Treg depletion compared to controls ( Gomez-Lopez et al., 2020 ). Therefore, the determination of maternal-fetal medicine parameters allows for a translational assessment of well-being in the mother and the fetus.…”

“…Herein, we provide a protocol that allows for the determination of body temperature, blood pressure, and the evaluation of uterine and umbilical arteries as well as maternal and fetal heart rate using high-resolution ultrasound in pregnant mice. For complete details on the use and execution of this protocol, please refer to Gomez-Lopez et al. (2020) .…”

“…For complete details on the use and execution of this protocol, please refer to Gomez-Lopez et al. (2020) .…”

Immune regulation at the foetal-maternal interface; implications for healthy and complicated pregnancies

“…Furthermore, depletion of systemic Treg cells increased the incidence of preterm birth in mice, which was rescued by adoptive Treg cell transfer. Systemic depletion of Treg cells also increased susceptibility to LPS-induced preterm birth (170).…”