Cell type-specific enhancers regulate IL-22 expression in innate and adaptive type 3 lymphoid cells

IL-22, a signature cytokine for type 3 lymphoid cells, including T helper 17/22 (Th17/22) and type 3 innate lymphoid cells (ILC3), mediates epithelial homeostasis and protective pathogen responses in barrier tissues. Upon dysregulation, IL-22 can drive chronic inflammatory diseases, yet little is known about transcriptional elements modulating its expression. Here, we identify two enhancers, E22-1 and E22-2, with distinct capacities for regulating Il22 expression in type 3 lymphoid cells. Both enhancers are necessary for protection from Citrobacter rodentium infection and for the onset of IL-22-mediated psoriasis. E22-2 is specifically required for IL-22 expression in ILC3s, while E22-1 functions in both Th17/22 and ILC3. The ILC3 specificity of E22-2 is attributed to the presence of multiple Runx3 sites and the lack of a functional RORγt motif. We conclude that Th17/22 and ILC3 cells use distinct cis-elements to differentially regulate IL-22 expression, while orchestrating homeostatic protection and pathogen defense in barrier tissues. In healthy barrier tissues, type 3 lymphoid cells express IL-22 to maintain a protective immune balance, while IL-22 dysregulation contributes to disease. Here, the authors identify E22-1 and E22-2 as enhancers regulating IL-22 expression in health and disease; with E22-2 being restricted to IL-22 regulation in ILC3s.