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

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 (PTB), which is accompanied by a concomitant increase in Tc17 cells. In mice, depletion of functional Tregs during late gestation induced PTB and adverse neonatal outcomes, which were rescued by the adoptive transfer of such cells. Treg depletion did not alter obstetrical parameters in the mother; yet, it increased susceptibility to endotoxin-induced PTB. The mechanisms whereby the loss of Tregs induces adverse perinatal outcomes involved 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 central role for Tregs in the pathophysiology of idiopathic PTB and adverse neonatal outcomes. RNAseq was used to survey the molecular processes dysregulated in the placenta upon Treg depletion [n=5 per group, Partial Treg-depleted (25 μg/kg) Foxp3DTR dams, Total Treg-depleted (50 μg/kg) Foxp3DTR dams, and non-Treg-depleted (PBS) controls]