T-bet inhibits both TH2 cell–mediated eosinophil recruitment and TH17 cell–mediated neutrophil recruitment into the airways

BackgroundPrevious studies have shown that mice lacking T-bet, a critical transcription factor for TH1 cell differentiation, spontaneously develop airway inflammation with intense eosinophil infiltrates. However, the mechanism underlying T-bet–mediated inhibition of allergic airway inflammation is still unknown.ObjectiveTo determine the regulatory role of T-bet in antigen-induced allergic airway inflammation.MethodsWe examined the role of T-bet in antigen-induced allergic airway inflammation using T-bet−/− mice on a BALB/c background that did not develop spontaneous airway inflammation. We also examined the role of T-bet expression of CD4+ T cells in airway inflammation by adoptive transfer experiments.ResultsWe found that antigen-induced eosinophil recruitment, goblet cell hyperplasia, and TH2 cytokine production in the airways were enhanced in T-bet−/− mice. However, in the absence of signal transducer and activator of transcription 6 (STAT6), T-bet deficiency could not induce the antigen-induced eosinophilic airway inflammation. Adoptive transfer of T-bet−/− or T-bet+/+ CD4+ T cells to T-bet−/−Rag-2−/− mice revealed that the expression of T-bet in CD4+ T cells was vital for the inhibition of antigen-induced eosinophilic airway inflammation. Interestingly, antigen-induced neutrophil recruitment in the airways was also enhanced in T-bet−/− mice. Moreover, T-bet−/− CD4+ T cells preferentially differentiated into IL-17–producing cells that mediated neutrophilic airway inflammation.ConclusionT-bet inhibits both TH2 cell–mediated eosinophilic inflammation and TH17 cell–mediated neutrophilic inflammation in the airways.Clinical implicationsThe dysfunction of T-bet may be involved in the pathogenesis of severe asthma, in which accumulation of neutrophils as well as eosinophils in the airways is a hallmark of disease.