E3 ubiquitin ligase Cbl-b plays a crucial role in T cell activation and tolerance induction. However, the molecular mechanism by which Cbl-b inhibits T cell activation remains unclear. Here, we report that Cbl-b does not inhibit PI3K but rather suppresses TCR/CD28-induced inactivation of Pten. The elevated Akt activity in Cbl-b−/− T cells is therefore due to heightened Pten inactivation. Suppression of Pten inactivation in T cells by Cbl-b is achieved by impeding the association of Pten with Nedd4, which targets Pten K13 for K63-linked polyubiquitination. Consistent with this finding, introducing Nedd4 deficiency into Cbl-b−/− mice abrogates hyper-T cell responses caused by the loss of Cbl-b. Hence, our data demonstrate that Cbl-b inhibits T cell activation by suppressing Pten inactivation independently of its ubiquitin ligase activity.
Graphical Abstract
Highlights
► Cbl-b inhibits TCR-induced Akt activation in T cells ► This process is not due to the suppression of PI3K, but defective Pten inactivation ► Cbl-b suppresses Pten ubiquitination by impeding the binding of Pten to Nedd4 ► Nedd4 deficiency abrogates hyper-T cell responses in Cbl-b−/− mice