IL-33-binding HpARI family homologues with divergent effects in suppressing or enhancing type 2 immune responses
Florent Colomb, Adefunke Ogunkanbi, Abhishek Jamwal, Beverly Dong, Rick M. Maizels, Constance A. M. Finney, James D. Wasmuth, Matthew K. Higgins, Henry J. McSorley
Abstract
ABSTRACT HpARI is an immunomodulatory protein secreted by the intestinal nematode Heligmosomoides polygyrus bakeri , which binds and blocks IL-33. Here, we find that the H. polygyrus bakeri genome contains three HpARI family members and that these have different effects on IL-33-dependent responses in vitro and in vivo , 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 in vivo . Together, these data show that H. polygyrus bakeri secretes a family of HpARI proteins with both overlapping and distinct functions, comprising a complex immunomodulatory arsenal of host-targeted proteins.