ILC3s sense gut microbiota through STING to initiate immune tolerance

Immune tolerance to gut microbiota is necessary for health, yet the mechanisms initiating it remain elusive. We profiled MHC II⁺ cells at single-cell resolution from the large intestine. Following colonization with the pathobiont Helicobacter hepaticus, group 3 innate lymphoid cells (ILC3s) were a key RORγt⁺ antigen-presenting cell that expressed low levels of pattern-recognition receptors but upregulated signatures for antigen presentation and STING signaling. We revealed that STING signaling in ILC3s permitted direct sensing of microbes and enhanced CCR7-dependent migration to gut-draining lymph nodes. ILC3-intrinsic STING signaling supported the instruction of microbiota-specific regulatory T cells and restrained chronic inflammation. However, gut inflammation induced exuberant STING activation, which resulted in the cell death of ILC3s. Our results define STING as a key sensor of gut microbiota in ILC3s. At steady state, this endows ILC3s with the ability to instruct immune tolerance, but heightened STING activation becomes detrimental and eliminates this tissue-protective cell type.