Adenosine metabolized from extracellular ATP promotes type 2 immunity through triggering A2BAR signaling on intestinal epithelial cells

Multicellular intestinal nematode parasites can cross the epithelial barrier potentially causing tissue damage and release of danger associated molecular patterns (DAMPs) that may promote type 2 responses and host protective immunity. We investigated whether adenosine specifically binding the A2B adenosine receptor (A2BAR) on epithelial cells played an important role in driving intestinal immunity. Specific blockade of epithelial cell A2BAR inhibited the host protective memory response to the enteric helminth, Heligmosomoides polygyrus bakeri, including disruption of granuloma development at the host:parasite interface during the transient tissue dwelling larval stage. Memory T cell development was blocked during the primary response and transcriptional analyses revealed profound impairment of A2BAR signaling in epithelial cells and reduced type 2 markers by 24 hours after inoculation. Extracellular ATP was visualized by 24 hours after inoculation and shown in CD39 deficient mice to be critical for the adenosine production mediating initiation of type 2 immunity.