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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE145357 | GEO | 2020/06/04

REPOSITORIES: GEO

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Project description:Preterm birth (PTB, born before 37 weeks of gestation) is a leading cause of neonatal mortality and post-natal morbidity. PTB affects one in nine all live births in the U.S. Notably, the highest rate of PTB occurs among African Americans (one in six). PTB is a complex trait, likely determined by multiple environmental and genetic factors and their interactions. We demonstrated strong familial aggregation of preterm and low birthweight in the US Blacks and Whites (Wang et al, NEJM, <a href="http://www.ncbi.nlm.nih.gov/pubmed/7491139">1995</a>) and conducted the largest candidate gene study of preterm birth at that time (Hao et al, HMG, <a href="http://www.ncbi.nlm.nih.gov/pubmed?cmd=DetailsSearch&term=14976157">2004</a>). We showed that a subset of mothers with certain metabolic gene variants are particularly vulnerable to the adverse effects of cigarette smoking on low birthweight and preterm births (Wang et al, JAMA, <a href="http://www.ncbi.nlm.nih.gov/pubmed?cmd=DetailsSearch&term=11779261">2002</a>). We also published a number of papers that examined the effect of maternal pre-pregnancy BMI, micronutrient status, stress and environmental toxins on the risk of preterm birth and related conditions. This project, supported by a grant from the NICHD (2R01HD41702, PI, Xiaobin Wang), aimed to conduct a genome-wide association study (GWAS) and apply advanced statistical methods to identify susceptibility loci of PTB in a predominantly urban low-income African American sample, a subset of the Boston Birth Cohort. PUBLIC HEALTH REVELANCE: We anticipate that this study will lead to the identification of novel genetic loci of PTB and gene-environment interactions. Such findings not only will provide important insights into mechanisms leading to PTB, but also may help identify women at high-risk of PTB, which in turn, may lead to the development of early and targeted interventions that can prevent PTB or mitigate the severity and consequences of PTB.

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

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