Role of IL-4 receptor [alpha]-positive CD4+T cells in chronic airway hyperresponsiveness

Background TH2 cells and their cytokines are associated with allergic asthma in human subjects and with mouse models of allergic airway disease. IL-4 signaling through the IL-4 receptor α (IL-4Rα) chain on CD4+T cells leads to TH2 cell differentiationin vitro, implying that IL-4Rα-responsive CD4+T cells are critical for the induction of allergic asthma. However, mechanisms regulating acute and chronic allergen-specific TH2 responsesin vivoremain incompletely understood. Objective This study defines the requirements for IL-4Rα-responsive CD4+T cells and the IL-4Rα ligands IL-4 and IL-13 in the development of allergen-specific TH2 responses during the onset and chronic phase of experimental allergic airway disease. Methods Development of acute and chronic ovalbumin (OVA)-induced allergic asthma was assessed weekly in CD4+T cell-specific IL-4Rα-deficient BALB/c mice (LckcreIL-4Rα-/lox) and respective control mice in the presence or absence of IL-4 or IL-13. Results During acute allergic airway disease, IL-4 deficiency did not prevent the onset of TH2 immune responses and OVA-induced airway hyperresponsiveness or goblet cell hyperplasia, irrespective of the presence or absence of IL-4Rα-responsive CD4+T cells. In contrast, deficiency of IL-13 prevented allergic asthma, irrespective of the presence or absence of IL-4Rα-responsive CD4+T cells. Importantly, chronic allergic inflammation and airway hyperresponsiveness were dependent on IL-4Rα-responsive CD4+T cells. Deficiency in IL-4Rα-responsive CD4+T cells resulted in increased numbers of IL-17-producing T cells and, consequently, increased airway neutrophilia. Conclusion IL-4-responsive T helper cells are dispensable for acute OVA-induced airway disease but crucial in maintaining chronic asthmatic pathology.