E3 ubiquitin ligase Cbl-b negatively regulates T helper 2 cell responses by targeting Stat-6 for ubiquitination (152.19)

Abstract

Abstract Casitas-B-lineage lymphoma protein-b (Cbl-b), an E3 ubiquitin ligase, belongs to the Cbl family. Recent studies indicate that Cbl-b emerges as a gatekeeper that controls the activation threshold of the antigen receptor and maintains the balance between tolerance and autoimmunity. However, the role of Cbl-b in T helper (Th) cell differentiation remains unknown. In this study, we show that Cbl-b deficiency selectively results in a biased Th2 differentiation in vitro. Furthermore, using a mouse model of asthma, we find that the absence of Cbl-b results in severe airway inflammation which associates with stronger Th2 responses including elevated IL-4, IL-5, and IL-13, and accumulation of eosinophils in bronchoalveolar lavage (BAL) fluid and higher titers of IgE in the serum. At the molecular level, Cbl-b selectively associates with Stat-6 upon IL-4 ligation, and targets Stat-6 for K48-linked polyubiquitination and subsequently degradation in the proteasome. These processes are heightened in the presence of TCR/CD28 costimulation. IL-4-induced Cbl-b-Stat6 association requires Cbl-b TKB domain, whereas TCR/CD28-induced Cbl-b-Stat6 interaction is mediated by tyrosine residues of Cbl-b and SH2 domain of Stat6. Therefore, we have discovered a previously uncharacterized function of Cbl-b in Th2 cell differentiation that may serve as an important therapeutic target for allergic diseases including asthma.