IL-13 induces airways hyperreactivity independently of the IL-4R alpha chain in the allergic lung

The potent spasmogenic properties of IL-13 have identified this molecule as a potential regulator of airways hyperreactivity (AHR) in asthma. Although IL-13 is thought to primarily signal through the IL-13R alpha1-IL-4R alpha complex, the cellular and molecular components employed by this cytokine t o induce AHR in the allergic lung have not been identified. By transferring OVA-specific CD4(+) T cells that were wild type (IL-13(+/+) T cells) or de ficient in IL-13 (IL-13(-/-) T cells) to nonsensitized mice that were then challenged with OVA aerosol, we show that T cell-derived IL-13 plays a key role in regulating AHR, mucus hypersecretion, eotaxin production, and eosin ophilia in the allergic lung. Moreover, IL-13(+/+) T cells induce these fea tures (except mucus production) of allergic disease independently of the IL -4R alpha chain. By contrast, IL-13(+/+) T cells did not induce disease in STAT6-deficient mice. This shows that IL-13 employs a novel component of th e IL-13 receptor signaling system that involves STAT6, independently of the IL-4R alpha chain, to modulate pathogenesis. We show that this novel pathw ay for IL-13 signaling is dependent on T cell activation in the lung and is critically linked to downstream effector pathways regulated by eotaxin and STAT6.