ILC3s sense gut microbiota through STING to initiate immune tolerance

Wenqing Zhou; Jordan Z Zhou; Anees Ahmed; Myeong Joon Kim; JRI Live Cell Bank; Chun-Jun Guo; Gregory F Sonnenberg

doi:10.1016/j.immuni.2025.05.016

ILC3s sense gut microbiota through STING to initiate immune tolerance

Immunity. 2025 Jun 13:S1074-7613(25)00237-7. doi: 10.1016/j.immuni.2025.05.016. Online ahead of print.

Authors

Wenqing Zhou¹, Jordan Z Zhou², Anees Ahmed², Myeong Joon Kim²; JRI Live Cell Bank³; Chun-Jun Guo², Gregory F Sonnenberg⁴

Affiliations

¹ Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology and Hepatology, Weill Cornell Medicine, Cornell University, New York, NY, USA; Department of Microbiology & Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA; Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA. Electronic address: wez4003@med.cornell.edu.
² Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology and Hepatology, Weill Cornell Medicine, Cornell University, New York, NY, USA; Department of Microbiology & Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA; Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA.
³ Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA.
⁴ Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology and Hepatology, Weill Cornell Medicine, Cornell University, New York, NY, USA; Department of Microbiology & Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA; Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA. Electronic address: gfsonnenberg@med.cornell.edu.

PMID: 40527323
DOI: 10.1016/j.immuni.2025.05.016

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.