title: IL-33 drives biphasic IL-13 production for noncanonical Type 2 immunity against hookworms.
abstract: Parasitic helminths are a major cause of chronic human disease, affecting more than 3 billion people worldwide. Host protection against most parasitic helminths relies upon Type 2 cytokine production, but the mechanisms that regulate interleukin (IL) 4 and 13 production from CD4(+) T helper 2 cells (T(H)2) and innate lymphoid type 2 cells (ILC2s) remain incompletely understood. The epithelial cell-derived cytokines IL-25 and IL-33 promote Type 2 responses, but the extent of functional redundancy between these cytokines is unclear and whether Type 2 memory relies upon either IL-25 or IL-33 is unknown. Herein, we demonstrate a pivotal role for IL-33 in driving primary and anamnestic immunity against the rodent hookworm Nippostrongylus brasiliensis. IL-33-deficient mice have a selective defect in ILC2-derived IL-13 during both primary and secondary challenge infections but generate stronger canonical CD4(+) T helper 2 cells responses (IL-4, IgE, mast cells, and basophils) than WT controls. Lack of IL-13 production in IL-33-deficient mice impairs resistin-like molecule beta (RELMβ) expression and eosinophil recruitment, which are two mechanisms that eliminate N. brasiliensis parasites from infected hosts. Thus, IL-33 is requisite for IL-13 but not IL-4-driven Type 2 responses during hookworm infection.
authors.affiliation: Division of Experimental Medicine, University of California, San Francisco, CA 94110, USA.
authors.forename: Li-Yin
authors.initials: LY
authors.lastname: Hung
authors.forename: Ian P
authors.initials: IP
authors.lastname: Lewkowich
authors.forename: Lucas A
authors.initials: LA
authors.lastname: Dawson
authors.forename: Jordan
authors.initials: J
authors.lastname: Downey
authors.forename: Yanfen
authors.initials: Y
authors.lastname: Yang
authors.forename: Dirk E
authors.initials: DE
authors.lastname: Smith
authors.forename: De'Broski R
authors.initials: DR
authors.lastname: Herbert
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D004804:Eosinophils / Q000276:immunology; D005434:Flow Cytometry; D006725:Hookworm Infections / Q000276:immunology*; D006729:Hormones, Ectopic / Q000276:immunology; D036341:Intercellular Signaling Peptides and Proteins; D018793:Interleukin-13 / Q000276:immunology*; D000067596:Interleukin-33; D007378:Interleukins / Q000172:deficiency / Q000276:immunology*; D051379:Mice; D009559:Nippostrongylus / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D006729:Hormones, Ectopic; C506535:Il33 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D018793:Interleukin-13; D000067596:Interleukin-33; D007378:Interleukins; C486522:Retnlb protein, mouse