Structural basis for IL-33 recognition and its antagonism by the helminth effector protein HpARI2

IL-33 plays a significant role in inflammation, allergy, and host defence against parasitic helminths. The model gastrointestinal nematode Heligmosomoides polygyrus bakeri secretes the Alarmin Release Inhibitor HpARI2, an effector protein that suppresses protective immune responses and asthma in its host byinhibiting IL-33 signalling. Here we reveal the structure of HpARI2 bound to mouse IL-33. HpARI2 contains three CCP-like domains, and we show that it contacts IL-33 primarily through the second and third of these. A large loop which emerges from CCP3 directly contacts IL-33 and structural comparison showsthatthisoverlapswiththebindingsiteonIL-33foritsreceptor,ST2, preventing formation of a signalling complex. Truncations of HpARI2 which lack thelargeloopfromCCP3arenotabletoblockIL-33-mediatedsignallingin a cell-based assay and in an in vivo female mousemodelofasthma.Thisshows that direct competition between HpARI2 and ST2 is responsible for suppression of IL-33-dependent responses.