IL-33-binding HpARI family homologues with divergent effects in suppressing or enhancing type 2 immune responses.

HpARI is an immunomodulatory protein secreted by the intestinal nematode , which binds and blocks IL-33. Here, we find that the genome contains three HpARI family members and that these have different effects on IL-33-dependent responses and , with HpARI1+2 suppressing and HpARI3 amplifying these responses. All HpARIs have sub-nanomolar affinity for mouse IL-33; however, HpARI3 does not block IL-33-ST2 interactions. Instead, HpARI3 stabilizes IL-33, increasing the half-life of the cytokine and amplifying responses to it . Together, these data show that secretes a family of HpARI proteins with both overlapping and distinct functions, comprising a complex immunomodulatory arsenal of host-targeted proteins.