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. 2025 Jul 8;58(7):1762-1777.e7.
doi: 10.1016/j.immuni.2025.05.016. Epub 2025 Jun 16.

ILC3s sense gut microbiota through STING to initiate immune tolerance

Wenqing Zhou  1 , Jordan Z Zhou  2 , Anees Ahmed  2 , Myeong Joon Kim  2 ; JRI Live Cell Bank  3 ; Chun-Jun Guo  2 , Gregory F Sonnenberg  4
Affiliations

ILC3s sense gut microbiota through STING to initiate immune tolerance

Wenqing Zhou et al. Immunity. .

Abstract

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.

Keywords: IBD; ILC3s; RORγt(+) antigen-presenting cells; STING; chronic inflammation; immune tolerance; microbiota.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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