PKC-
Modulates the Strength of T Cell Responses by Targeting Cbl-b for Ubiquitination and Degradation
Thomas Gruber1,
Natascha Hermann-Kleiter1,
Reinhard Hinterleitner1,
Friedrich Fresser1,
Rainer Schneider2,
Günther Gastl3,
Josef M. Penninger4, and
Gottfried Baier1*
1 Department of Medical Genetics, Clinical and Molecular Pharmacology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
2 Institute of Biochemistry, University of Innsbruck, 6020 Innsbruck, Austria.
3 Laboratory of Tumor Immunology, Department of Hematology and Oncology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
4 Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.
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-
(PKC-) as the critical intermediary for the inactivation of Cbl-b in response to costimulation of T cells through CD28. PKC- 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-. Consistent with this mechanism, the impaired responses of PKC-deficient T cells were at least partially restored by the concomitant genetic loss of cblb. Thus, our data establish a nonredundant antagonism between PKC- and Cbl-b that regulates T cell activation responses.
* To whom correspondence should be addressed. E-mail: gottfried.baier{at}i-med.ac.at
