Research ArticleImmunology

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

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Sci. Signal.  23 Jun 2009:
Vol. 2, Issue 76, pp. ra30
DOI: 10.1126/scisignal.2000046

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Abstract

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.

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