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

尽管在产前和孕产妇保健方面取得了进展，但妊娠并发症和早产的发生率 在美国仍然居高不下。母体对胎儿的免疫耐受性对促进胎儿生长至关重要， 但胎儿免疫细胞发育的调控机制在很大程度上仍不清楚。干扰素 是胎盘形成的关键调节因素，但过度的干扰素反应会导致胎儿吸收。此外, 母亲的中性粒细胞减少经常与妊娠并发症有关，如先兆子痫，这有 已被证明会对胎儿和新生儿产生不利影响。我们对中性粒细胞功能的认识 在母婴交界处，除了它们在感染中的常规作用外，仍然非常有限。肠道微生物群 在怀孕期间经历了剧烈的变化。然而，母体肠道微生物免疫耐受的作用 胎儿的免疫调节仍然知之甚少。我们已经开发出新的技术来分离和 研究妊娠小鼠胎盘免疫细胞的特征。基于我们对母体MDSC的新发现- 干扰素γ轴在由肠道微生物群协调的母胎界面，目前的提议旨在 明确母体肠道微生物组驱动的mdsc-干扰素γ轴在胎儿和新生儿免疫发育中的作用。 利用我们实验室建立的方法学来分离和描述免疫细胞的转录组，我们 将使用一种公正和全面的方法来充分了解胎儿免疫功能的变化 由于肠道微生物群的扰动而造成的景观。转录研究将与体外实验相结合。 从胎盘和胎儿/新生儿肠道分离的组织免疫细胞的功能研究 驱动母婴免疫细胞变化的特定肠道细菌和代谢产物的研究 界面。首先，我们将使用一种公正的方法来描述胎儿免疫细胞的转录组 胎儿肝脏和肠道间充质干细胞干扰素γ轴在母体免疫细胞调节中的作用 这些胎儿组织中的发育。其次，我们将调查在怀孕期间缺乏母体MDSCs的情况 影响出生后肠道免疫发育，并研究T细胞的免疫印迹 子宫中过量的干扰素γ信号，并评估它如何影响后代对肠道炎症的易感性。 完成后，这些研究将确定母体肠道微生物组的作用，通过调节 干扰素γ轴，塑造胎儿免疫格局和新生儿肠道免疫发育。我们的 研究将确定特定的胎儿免疫亚群，这些免疫亚群容易受到干扰的msc-干扰素γ轴的影响， 成为潜在的治疗/干预目标。我们的研究结果将为未来提供框架 靶向操纵肠道微生物群调节这些免疫途径促进胎儿发育的研究 免疫细胞发育。

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.