LAUSR

Significance Group 3 innate lymphoid cells (ILC3s) mediate immune responses in bacterial infections and autoimmunity. Intestinal ILC3s encounter metabolic signals derived from the diet and microbiota, yet the impact of these metabolites on ILC3s is unclear. Here we demonstrate that polyamines and their associated metabolic pathways are enriched in ILC3s. Treatment with putrescine, a key polyamine species, enhanced ILC3 production of IL-22. Conditional deletion of ornithine decarboxylase 1 (ODC1), the rate-limiting enzyme in polyamine biosynthesis, in ILC3s reduced IL-22 expression and increased mice susceptibility to infection by Citrobacter rodentium. In an autoimmune colitis model, ODC1 deficiency in ILC3s protected mice from colitis by reducing IL-22 production. We conclude that ILC3 polyamine biosynthesis is a promising therapeutic target for intestinal infections and autoinflammatory disorders.