Julia A. Brown, Mohammed Amir, Shui Yu, Daniel Wong, Jinghua Gu, Uthra Balaji, Christopher N. Parkhurst, Seunghee Hong, Lucy R. Hart, Hannah C. Carrow, Mamadou A. Bah, Aparna Ananthanarayanan, Katherine Z. Sanidad, Mengze Lyu, Anisa Siddikova, Marina L. S. Santos, Inna Serganova, Gretchen E. Diehl, Josef Anrather, Naohiro Inohara, Gregory F. Sonnenberg, Virginia Pascual, Melody Y. Zeng
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.