PKC-theta modulates the strength of T cell responses by targeting Cbl-b for ubiquitination and degradation.
Article Details
- CitationCopy to clipboard
Gruber T, Hermann-Kleiter N, Hinterleitner R, Fresser F, Schneider R, Gastl G, Penninger JM, Baier G
PKC-theta modulates the strength of T cell responses by targeting Cbl-b for ubiquitination and degradation.
Sci Signal. 2009 Jun 23;2(76):ra30. doi: 10.1126/scisignal.2000046.
- PubMed ID
- 19549985 [ View in PubMed]
- 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-theta (PKC-theta) as the critical intermediary for the inactivation of Cbl-b in response to costimulation of T cells through CD28. PKC-theta 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-theta. Consistent with this mechanism, the impaired responses of PKCtheta-deficient T cells were at least partially restored by the concomitant genetic loss of cblb. Thus, our data establish a nonredundant antagonism between PKC-theta and Cbl-b that regulates T cell activation responses.