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

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.