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.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / immunology*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • CD28 Antigens / genetics
  • CD28 Antigens / immunology
  • CD28 Antigens / metabolism
  • Isoenzymes / genetics
  • Isoenzymes / immunology*
  • Isoenzymes / metabolism
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology*
  • Mice
  • Mice, Knockout
  • Protein Kinase C / genetics
  • Protein Kinase C / immunology*
  • Protein Kinase C / metabolism
  • Protein Kinase C-theta
  • Proto-Oncogene Proteins c-cbl / genetics
  • Proto-Oncogene Proteins c-cbl / immunology*
  • Proto-Oncogene Proteins c-cbl / metabolism
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism
  • T-Lymphocytes / enzymology
  • T-Lymphocytes / immunology*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / immunology*
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination / genetics
  • Ubiquitination / immunology*


  • Adaptor Proteins, Signal Transducing
  • CD28 Antigens
  • Cblb protein, mouse
  • Isoenzymes
  • Receptors, Antigen, T-Cell
  • Proto-Oncogene Proteins c-cbl
  • Ubiquitin-Protein Ligases
  • Prkcq protein, mouse
  • Protein Kinase C
  • Protein Kinase C-theta