ILC3s as central regulators of mucosal homeostasis and disease pathogenesis (Review).

Abstract

Type 3 innate lymphoid cells (ILC3s) constitute key components of mucosal innate immunity and serve key roles in maintaining mucosal barrier homeostasis and regulating inflammatory responses. The present review summarizes the biological characteristics and regulatory mechanisms of ILC3s, while discussing their interactions with the gut microbiota and pathological functions in mucosa‑associated disorders. Derived from bone marrow‑resident common lymphoid progenitors, ILC3s differentiate under the transcriptional control of retinoid‑related orphan receptor γ‑t into distinct functional subsets, including natural cytotoxicity receptor (NCR)+ ILC3s, NCR‑ ILC3s and lymphoid tissue inducer cells. ILC3s maintain epithelial barrier integrity, enhance antimicrobial defense and support lymphoid tissue development through the production of effector molecules such as IL‑22, IL‑17 and granulocyte‑macrophage colony‑stimulating factor. These subsets can undergo phenotypic conversion in response to microenvironmental signals. ILC3 activity is tightly regulated by transcription factors, metabolic pathways, neuroimmune interactions and the circadian clock system. In addition, ILC3s establish bidirectional interactions with the gut microbiota: Microbial metabolites regulate ILC3 activity, whereas ILC3s influence microbial composition through IL‑22‑dependent antimicrobial peptide production and IgA responses. Depending on subset composition, local cytokine networks and tissue microenvironment, ILC3s may exert either pathogenic or protective effects in a number of diseases. Future investigations should aim to further elucidate the molecular mechanisms underlying ILC3 subset plasticity, tissue‑specific interaction networks and clinically translatable strategies for targeted intervention. Building upon these findings, the present review proposes a spatiotemporal‑quantitative framework and three regulatory axes that may account for disease‑specific variations in ILC3 responses, providing a basis for understanding distinct ILC3 functions and developing targeted therapeutic strategies. Systematic investigation of the regulatory principles governing ILC3 biology will not only deepen the understanding of innate immune homeostasis but also provide potential targets and strategies for precision immunotherapy in diseases such as inflammatory bowel disease and colorectal cancer.