Gut-derived, inflammatory ILC2s disseminate type 2 immunity to remote lung in food allergen-challenged mice.

Dissemination of type 2 immunity along skin-gut-lung axes contributes to allergic march progressions in atopic individuals, yet the underlying mechanisms remain incompletely understood. In mice, gastrointestinal helminth infections can mobilize a circulating pool of gut-derived, inflammatory type 2 innate lymphoid cells (iILC2s), which, in turn, establish an early type 2 immune response in remote lung. Here, using the model allergen ovalbumin, we demonstrate duodenum-restricted expansion of iILC2s is similarly elicited in response to an ingested food allergen. Gut-derived iILC2s migrated to mesenteric lymph nodes and lung, wherein they positively correlated with local lung Il13 expression within 1 h of food-allergen ingestion. Duodenal iILC2 expansion was accompanied by duodenal tuft cell expansion and IL-25 production, and treatment with IL-25 recapitulated iILC2 expansion and lung migration in the absence of allergen. Inhibition of iILC2 migration attenuated the rapid food allergen- or IL-25-induced Il13 response and subsequent mucin dysregulation in remote lung. Eosinophil infiltration proceeded iILC2s into remote lungs by 24 h; however, neither pharmacologic nor genetic inhibition of iILC2s prevented food allergen- or IL-25-elicited eosinophil remote lung homing, decoupling eosinophil recruitment from iILC2s. Collectively, these data shed new light on type 2 immune dissemination along the gut-lung axis by revealing the duodenum as a regional hub for food allergen-driven expansion of iILC2s that rapidly reshape the remote lung cytokine milieu.