IL-33 amplifies both Th1- and Th2-type responses through its activity on human basophils, allergen-reactive Th2 cells, iNKT and NK cells

Int Immunol. 2008 Aug;20(8):1019-30. doi: 10.1093/intimm/dxn060. Epub 2008 Jun 11.


IL-33 is an IL-1 family member recently identified as the ligand for T1/ST2 (ST2), a member of the IL-1 receptor family. ST2 is stably expressed on mast cells and T(h)2 effector T cells and its function has been studied in the context of T(h)2-associated inflammation. Indeed, IL-33 induces T(h)2 cytokines from mast cells and polarized mouse T cells and leads to pulmonary and mucosal T(h)2 inflammation when administered in vivo. To better understand how this pathway modulates inflammatory responses, we examined the activity of IL-33 on a variety of human immune cells. Human blood-derived basophils expressed high levels of ST2 receptor and responded to IL-33 by producing several pro-inflammatory cytokines including IL-1 beta, IL-4, IL-5, IL-6, IL-8, IL-13 and granulocyte macrophage colony-stimulating factor. Next, utilizing a human T(h)2-polarized T cell culture system derived from allergic donor blood cells, we found that IL-33 was able to enhance antigen-dependent and -independent T cell responses, including IL-5, IL-13 and IFN-gamma production. IL-33 activity was also tested on V alpha 24-positive human invariant NKT (iNKT) cells. In the presence of alpha-galactosylceramide antigen presentation, IL-33 dose dependently enhanced iNKT production of several cytokines, including both IL-4 and IFN-gamma. IL-33 also directly induced IFN-gamma production from both iNKT and human NK cells via cooperation with IL-12. Taken together, these results indicate that in addition to its activity on human mast cells, IL-33 is capable of activating human basophils, polarized T cells, iNKT and NK cells. Moreover, the nature of the responses elicited by IL-33 suggests that this axis may amplify both T(h)1- and T(h)2-oriented immune responses.

MeSH terms

  • Antigens, Dermatophagoides*
  • Asthma / etiology
  • Asthma / immunology
  • Basophils / cytology
  • Basophils / immunology*
  • Basophils / metabolism
  • Cell Culture Techniques
  • Cytokines / immunology
  • Cytokines / metabolism
  • Escherichia coli*
  • Flow Cytometry
  • Galactosylceramides / pharmacology
  • Humans
  • Inflammation
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-33
  • Interleukins / immunology*
  • Interleukins / metabolism
  • Interleukins / pharmacology
  • Killer Cells, Natural / cytology
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Receptors, Cell Surface / immunology
  • Receptors, Cell Surface / metabolism
  • Recombinant Proteins / immunology*
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / pharmacology
  • Th2 Cells / cytology
  • Th2 Cells / immunology*
  • Th2 Cells / metabolism


  • Antigens, Dermatophagoides
  • Cytokines
  • Galactosylceramides
  • IL1RL1 protein, human
  • IL33 protein, human
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-33
  • Interleukins
  • Receptors, Cell Surface
  • Recombinant Proteins
  • alpha-galactosylceramide