T-bet and STAT6 Coordinately Suppress the Development of IL-9-Mediated Atopic Dermatitis-Like Skin Inflammation in Mice

T-bet and signal transducer and activator of transcription (STAT) 6 are critical factors for helper T-cell differentiation in humans and mice. Additionally, polymorphisms in TBX21 (T-bet) and STAT6 are associated with the susceptibility of allergic diseases. However, precise mechanisms of the reciprocal regulation between T-bet and STAT6 in allergy remain unclear. To determine the reciprocal regulation in vivo, we investigated the phenotype of T-bet/STAT6 double-deficient (T -bet(-/-) STAT6(-/-)) mice. Unexpectedly, T-bet(-/-) STAT6(-/-) mice but not T bet(-/-) miceor STAT6(-/-) mice spontaneously developed severe dermatitis. Not only eosinophils and mast cells but also CD4+ T cells infiltrated into the skin of T-bet(-/-) STAT6(-/-) mice. Adoptive transfer of CD4(+) T cells of T bet(-/-) STAT6(-/-) miceinto severe combined immunodeficient mice induced the accumulation of eosinophils and mast cells in the skin, whereas depletion of CD4(+) T cells ameliorated the dermatitis in T-bet(-/-) STAT6(-/-) mice. Comprehensive transcriptome analyses revealed that IL-9 expression was enhanced in T-bet(-/-) STAT6(-/-) CD4(+) T cells. Indeed, IL-9 neutralization ameliorated the dermatitis in T-bet(-/-) STAT6-/- mice. T-bet(-/-) STAT6(-/-) CD4(+) T cells expressed functional thymic stromal lymphopoietin receptors and produced large amounts of IL-9 on thymic stromal lymphopoietin stimulation. These results indicate that T-bet and STAT6 coordinately suppress atopic dermatitis-like skin inflammation, possibly by inhibiting thymic stromal lymphopoietin-dependent IL-9 production in CD4(+) T cells.