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LINGO4 coordinates intrinsic IL-22 production and microbiota-dependent ILC3 homeostasis to regulate intestinal immunity

ABSTRACT: LINGO4 is a leucine-rich repeat and immunoglobulin-like domain-containing transmembrane protein encoded immediately adjacent to Rorc, the gene for RORγt, raising the possibility that it contributes to the biology of RORγt⁺ lymphocytes. However, its impact on these cells and resistance to enteric infections has remained unknown. Here, we identify LINGO4 as a critical regulator of group 3 innate lymphoid cells (ILC3s). Lingo4–/– ILC3s exhibit a profound, cell-intrinsic defect in IL-22 production linked to impaired STAT3 activation, mitochondrial dysfunction, elevated reactive oxygen species, and increased apoptosis. In vivo, Lingo4 deficiency also drives a dysbiotic gut microbiota, resulting in an additional, microbiota-dependent loss of ILC3s. These combined defects increase susceptibility to C. difficile and C. rodentium, while Lingo4–/– driven IL-22 reduction confers protection against S. Typhimurium. Immunoprecipitation of tagged LINGO4 reveals interaction networks enriched in mitochondrial pathways, providing mechanistic insight into its role in ILC3 metabolic fitness and intestinal immunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE325926 | GEO | 2026/04/02

REPOSITORIES: GEO

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