IL-33 drives biphasic IL-13 production for noncanonical Type 2 immunity against hookworms

Proc Natl Acad Sci U S A. 2013 Jan 2;110(1):282-7. doi: 10.1073/pnas.1206587110. Epub 2012 Dec 17.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analysis of Variance
  • Animals
  • Eosinophils / immunology
  • Flow Cytometry
  • Hookworm Infections / immunology*
  • Hormones, Ectopic / immunology
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-13 / immunology*
  • Interleukin-33
  • Interleukins / deficiency
  • Interleukins / immunology*
  • Mice
  • Nippostrongylus / immunology*
  • Real-Time Polymerase Chain Reaction
  • Th2 Cells / immunology*


  • Hormones, Ectopic
  • Il33 protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-13
  • Interleukin-33
  • Interleukins
  • Retnlb protein, mouse