Gut microbiota promotes immune tolerance at the maternal-fetal interface

Abstract

Immune tolerance at the maternal-fetal interface (MFI) is required for fetal development. Excessive maternal interferon-gamma (IFN-γ) and interleukin-17 (IL-17) are linked to pregnancy complications, but the regulation of maternal IFN-γ and IL-17 at the MFI is poorly understood. Here, we demonstrate a gut-placenta immune axis in pregnant mice in which the absence or perturbation of gut microbiota dysregulates maternal IFN-γ and IL-17 responses at the MFI, resulting in fetal resorption. Microbiota-dependent tryptophan derivatives suppress IFN-γ+ and IL-17+ T cells at the MFI by priming myeloid-derived suppressor cells (MDSCs) and gut-derived RORγt+ regulatory T cells (Tregs), respectively. The tryptophan derivative indole-3-carbinol, or tryptophan-metabolizing Lactobacillus murinus, rebalances the T cell response at the MFI and reduces fetal resorption in germ-free mice. Furthermore, MDSCs, RORγt+ Tregs, and microbiota-dependent tryptophan derivatives are dysregulated at the MFI in human recurrent miscarriage cases. Together, our findings identify microbiota-dependent immune tolerance mechanisms that promote fetal development.

Keywords: MDSCs; T cells; Tregs; aryl hydrocarbon receptor; gut microbiota; gut-placenta axis; maternal-fetal immune tolerance; metabolites; tryptophan.