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PKC-θ Modulates the Strength of T Cell Responses by Targeting Cbl-b for Ubiquitination and Degradation

PKC-θ triggers the degradation of Cbl-b that is necessary for a full immune response in T cells. Degrading the Gatekeeper Full activation of T cells in vivo requires the simultaneous delivery of two independent signals: stimulation of the T cell receptor (TCR) by antigenic peptide presented by the major histocompatibility complex and stimulation of CD28 co-receptors. Stimulation of the TCR in the absence of a costimulatory signal results in a state of nonresponsiveness known as anergy, which is an important means of inhibiting the responses of self-reactive T cells that would otherwise trigger autoimmunity. The E3 ubiquitin ligase Cbl-b acts as a gatekeeper that prevents full activation of T cells by targeting proteins involved in TCR signaling for degradation (see the Perspective by Schmitz). Loss of cblb results in exacerbated autoimmune responses and enables activation of T cells through the TCR in the absence of costimulation of CD28. Cbl-b is itself targeted for ubiquitination and degradation in response to costimulation of CD28, but the mechanism involved is unclear. Gruber et al. found that protein kinase C-θ (PKC-θ), which is required for normal T cell immune responses, bound to Cbl-b on costimulation of CD28 and that PKC-θ–mediated phosphorylation of Cbl-b led to its ubiquitination and degradation. Experiments in which autoimmune disease was induced in mice singly or doubly deficient in cblb and PKCθ showed the antagonistic functions of Cbl-b and PKC-θ in regulating activation of T cells. Together, these data suggest that PKC-θ is critical for triggering the degradation of Cbl-b that is necessary to enable a full immune response in T cells. The E3 ubiquitin ligase Casitas B-lineage lymphoma (Cbl-b) is central to antigen-induced immune tolerance and regulates the CD28 dependence of T cell activation. Cbl-b undergoes ubiquitination and proteasomal degradation after adequate costimulation of T cells; however, the mechanism involved is unknown. Here, we identified protein kinase C-θ (PKC-θ) as the critical intermediary for the inactivation of Cbl-b in response to costimulation of T cells through CD28. PKC-θ associated with Cbl-b on stimulation of the T cell receptor. After costimulation of T cells through CD28, Cbl-b was ubiquitinated and degraded through a mechanism that depended on the kinase activity of PKC-θ. Consistent with this mechanism, the impaired responses of PKCθ-deficient T cells were at least partially restored by the concomitant genetic loss of cblb. Thus, our data establish a nonredundant antagonism between PKC-θ and Cbl-b that regulates T cell activation responses.