LINGO4 coordinates ILC3-intrinsic IL-22 production and microbiota-mediated ILC3 homeostasis.

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 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-/- 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.