The IL-21 receptor augments Th2 effector function and alternative macrophage activation

J Clin Invest. 2006 Jul;116(7):2044-55. doi: 10.1172/JCI27727. Epub 2006 Jun 15.


The IL-21 receptor (IL-21R) shows significant homology with the IL-4R, and CD4+ Th2 cells are an important source of IL-21. Here we examined whether the IL-21R regulates the development of Th2 responses in vivo. To do this, we infected IL-21R-/- mice with the Th2-inducing pathogens Schistosoma mansoni and Nippostrongylus brasiliensis and examined the influence of IL-21R deficiency on the development of Th2-dependent pathology. We showed that granulomatous inflammation and liver fibrosis were significantly reduced in S. mansoni-infected IL-21R-/- mice and in IL-21R+/+ mice treated with soluble IL-21R-Fc (sIL-21R-Fc). The impaired granulomatous response was also associated with a marked reduction in Th2 cytokine expression and function, as evidenced by the attenuated IL-4, IL-13, AMCase, Ym1, and FIZZ1 (also referred to as RELMalpha) responses in the tissues. A similarly impaired Th2 response was observed following N. brasiliensis infection. In vitro, IL-21 significantly augmented IL-4Ralpha and IL-13Ralpha1 expression in macrophages, resulting in increased FIZZ1 mRNA and arginase-1 activity following stimulation with IL-4 and IL-13. As such, these data identify the IL-21R as an important amplifier of alternative macrophage activation. Collectively, these results illustrate an essential function for the IL-21R in the development of pathogen-induced Th2 responses, which may have relevance in therapies for both inflammatory and chronic fibrotic diseases.

Publication types

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

MeSH terms

  • Animals
  • Cytokines / immunology
  • Female
  • Interleukin-21 Receptor alpha Subunit
  • Interleukins / immunology
  • Lung / anatomy & histology
  • Lung / immunology
  • Lung / parasitology
  • Lymph Nodes / immunology
  • Macrophage Activation*
  • Macrophages / immunology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nippostrongylus / immunology
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin / immunology*
  • Receptors, Interleukin-21
  • Schistosoma mansoni / immunology
  • Schistosomiasis mansoni / immunology
  • Signal Transduction / physiology
  • Strongylida Infections / immunology
  • Th1 Cells / immunology
  • Th2 Cells / immunology*


  • Cytokines
  • Il21r protein, mouse
  • Interleukin-21 Receptor alpha Subunit
  • Interleukins
  • Receptors, Interleukin
  • Receptors, Interleukin-21
  • interleukin-21