Grail controls Th2 cell development by targeting STAT6 for degradation

T helper (Th)-2 cells are the major players in allergic asthma; however, the mechanisms that control Th2-mediated inflammation are poorly understood. Here we find that enhanced expression of Grail, an E3 ubiquitin ligase, in Th2 cells depends on IL-4-signaling components, Stat6 and Gata3 that bind to and transactivate the Grail promoter. Grail-deficiency in T cells leads to increased expression of Th2 effector cytokines in vitro and in vivo and Grail deficient mice are more susceptible to allergic asthma. Mechanistically, the enhanced effector function of Grail-deficient Th2 cells is mediated by increased expression of Stat6 and IL-4 receptor α-chain. Grail interacts with Stat6 and targets it for ubiquitination and degradation. Thus, our results indicate that Grail plays a critical role in controlling Th2 development through a negative feedback loop.