Immune regulation by the gut microbiome at the maternal-fetal interface

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Despite advances in prenatal and maternal care, the incidence of pregnancy complications and preterm births remains high in the United States. Maternal immune tolerance toward the fetus is critical to promote fetal growth, but the regulatory mechanisms underlying fetal immune cell development remain largely undefined. Interferons are key regulators for placentation, but excessive interferon responses contribute to fetal resorption. In addition, maternal neutropenia is frequently associated with pregnancy complications such as preeclampsia, which has been demonstrated to affect the fetus and newborn adversely. Our understanding of the functions of neutrophils at the maternal-fetal interface, beyond their conventional role in infection, is still very limited. The gut microbiome undergoes drastic changes during pregnancy. However, the role of maternal gut microbiome immune tolerance and fetal immune regulation remains poorly understood. We have developed novel techniques to isolate and characterize placental immune cells in pregnant mice. Built upon our novel discovery of the maternal MDSC- IFNγ axis at the maternal-fetal interface that is orchestrated by the gut microbiome, the current proposal aims to define the role of maternal gut microbiome-driven MDSC-IFNγ axis in fetal and neonatal immune development. Leveraging the methodologies established in our lab to isolate and profile the transcriptome of immune cells, we will use an unbiased and comprehensive approach to fully appreciate functional changes in the fetal immune landscape due to perturbations of the gut microbiome. The transcriptomic studies will be coupled with ex vivo functional studies of tissue immune cells isolated from the placentas and fetal/neonatal intestines, as well as investigation of specific gut bacteria and metabolites that drive the immune cell changes at the maternal-fetal interface. First, we will employ an unbiased approach to profile the transcriptome of the fetal immune cells in the fetal liver and intestine to determine the role of the maternal MDSC-IFNγ axis in the regulation of immune cell development in these fetal tissues. Secondly, we will investigate how lacking maternal MDSCs during gestation impacts the postnatal immune development in the intestine, and investigate immune imprinting of T cells by in utero excessive IFNγ signaling and assess how it impacts the susceptibility to gut inflammation in the offspring. Upon completion, these studies will have defined the role of maternal gut microbiome, via regulation of the MDSC-IFNγ axis, shapes the fetal immune landscape and neonatal immune development in the intestine. Our studies will identify specific fetal immune subsets that are susceptible to perturbed MDSC-IFNγ axis that could be potential therapeutic/interventive targets. The findings from our studies will provide the framework for future studies of targeted manipulation of the gut microbiome to modulate these immune pathways to promote fetal immune cell development.