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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\u2212\/\u2212 ILC3s exhibit a profound, cell-intrinsic defect in IL-22 production linked to impaired STAT3 activation, mitochondrial dysfunction, elevated ROS, 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 Clostridioides difficile and Citrobacter rodentium, whereas IL-22 reduction in Lingo4\u2212\/\u2212 mice confers protection against Salmonellatyphimurium. Immunoprecipitation of tagged LINGO4 reveals interaction networks enriched in mitochondrial pathways, providing mechanistic insight into its role in ILC3 metabolic fitness and intestinal immunity.<\/jats:p>","DOI":"10.1084\/jem.20252632","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T06:20:59Z","timestamp":1775110859000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["LINGO4 coordinates ILC3-intrinsic IL-22 production and microbiota-mediated ILC3 homeostasis"],"prefix":"10.1084","volume":"223","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1035-5193","authenticated-orcid":true,"given":"Jos\u00e9 L.","family":"Fachi","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01yc7t268","id-type":"ROR","asserted-by":"publisher"}],"name":"Washington University in St. Louis, School of Medicine 1 Department of Pathology and Immunology, , Saint Louis, 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