E3 Ubiquitin Ligase Cbl-b Suppresses Proallergic T Cell Development and Allergic Airway Inflammation

E3 ubiquitin ligase Cbl-b has emerged as a gatekeeper that controls the activation threshold of the T cell antigen receptor and maintains the balance between tolerance and autoimmunity. Here, we report that the loss of Cbl-b facilitates T helper 2 (Th2) and Th9 cell differentiation in vitro. In a mouse model of asthma, the absence of Cbl-b results in severe airway inflammation and stronger Th2 and Th9 responses. Mechanistically, Cbl-b selectively associates with Stat6 upon IL-4 ligation and targets Stat6 for ubiquitination and degradation. These processes are heightened in the presence of T cell receptor (TCR)/CD28 costimulation. Furthermore, we identify K108 and K398 as Stat6 ubiquitination sites. Intriguingly, introducing Stat6 deficiency into Cblb−/− mice abrogates hyper-Th2 responses but only partially attenuates Th9 responses. Therefore, our data reveal a function for Cbl-b in the regulation of Th2 and Th9 cell differentiation. [Display omitted] •Loss of Cbl-b results in heightened Th2/Th9 responses and severe airway inflammation•Cbl-b is the E3 ubiquitin ligase for Stat6•Stat6 deficiency abrogates hyper-Th2 responses but partially impairs Th9 responses•Cbl-b regulates Th9 in both Stat6-dependent and -independent mechanisms The proallergic T cell subsets Th2 and Th9 cells are the major mediators of allergic airway inflammation. Here, Qiao, Zhang, and colleagues show that the E3 ubiquitin ligase Cbl-b suppresses allergic airway inflammation by targeting Stat6 for ubiquitination and proteasomal degradation, which leads to the inhibition of both Th2 and Th9 responses. They also find that inhibition of Th9 responses by Cbl-b involves both Stat6-dependent and -independent mechanisms. Therefore, Cbl-b is a potential drug target for treating allergic asthma.