A helminth-derived suppressor of ST2 blocks allergic responses

Abstract

The IL-33-ST2 pathway is an important initiator of type 2 immune responses. We previously characterised the HpARI protein secreted by the model intestinal nematode <i>Heligmosomoides polygyrus</i>, which binds and blocks IL-33. Here, we identify <i>H. polygyrus</i> Binds Alarmin Receptor and Inhibits (HpBARI) and HpBARI_Hom2, both of which consist of complement control protein (CCP) domains, similarly to the immunomodulatory HpARI and Hp-TGM proteins. HpBARI binds murine ST2, inhibiting cell surface detection of ST2, preventing IL-33-ST2 interactions, and inhibiting IL-33 responses in vitro and in an in vivo mouse model of asthma. In <i>H. polygyrus</i> infection, ST2 detection is abrogated in the peritoneal cavity and lung, consistent with systemic effects of HpBARI. HpBARI_Hom2 also binds human ST2 with high affinity, and effectively blocks human PBMC responses to IL-33. Thus, we show that <i>H. polygyrus</i> blocks the IL-33 pathway via both HpARI which blocks the cytokine, and also HpBARI which blocks the receptor.