IL-21 receptor signalling partially mediates Th2-mediated allergic airway responses

Clin Exp Allergy. 2014 Jul;44(7):976-85. doi: 10.1111/cea.12341.


Background: Interleukin-21 (IL-21) has been implicated in the development of Th2-mediated immune responses; however, the exact role it plays in allergic diseases is not well understood.

Objective: To elucidate the contribution of IL-21 receptor signalling to Th2-dependent immune responses in the lung.

Methods: We compared allergic airway responses in wild-type BALB/c and Il21r-deficient mice exposed to local airway challenge with house dust mite (HDM).

Results: We demonstrate that IL-21R-deficiency reduces HDM-driven airway hyperresponsiveness (AHR) with only partial effects on airway inflammation. Concomitant with the reduction in AHR in Il21r-deficient mice, significant suppression was observed in protein levels of the Th2 cytokines IL-4, and IL-13. In contrast, IL-21R-deficiency was associated with an increase in PBS- and allergen-driven IgE levels, while IgG1 and IgG2a levels were decreased. Moreover, our results suggest that IL-21 may contribute to AHR through its ability to both directly induce Th2 cell survival and to impair regulatory T-cell suppression of Th2 cytokine production. Importantly, we show that IL-21-positive cells are increased in the bronchial mucosa of asthmatics compared with non-asthmatics.

Conclusion: These results suggest that IL-21 plays an important role in the allergic diathesis by enhancing Th2 cytokine production through multiple mechanisms including the suppression of Treg inhibitory effects on Th2 cell cytokine production.

Keywords: IL-21; IL-21R; Tregs; airway hyperresponsiveness; asthma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allergens / immunology
  • Animals
  • Bronchial Hyperreactivity / genetics
  • Bronchial Hyperreactivity / immunology
  • Bronchial Hyperreactivity / metabolism
  • Cytokines / metabolism
  • Disease Models, Animal
  • Female
  • Hypersensitivity / genetics
  • Hypersensitivity / immunology*
  • Hypersensitivity / metabolism*
  • Immunoglobulin E / immunology
  • Immunoglobulin E / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Receptors, Interleukin-21 / deficiency
  • Receptors, Interleukin-21 / genetics
  • Receptors, Interleukin-21 / metabolism*
  • Signal Transduction*
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism
  • Th2 Cells / immunology*
  • Th2 Cells / metabolism*


  • Allergens
  • Cytokines
  • Receptors, Interleukin-21
  • Immunoglobulin E