PKC-theta modulates the strength of T cell responses by targeting Cbl-b for ubiquitination and degradation.
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.
Gruber
Thomas
T
Department of Medical Genetics, Clinical and Molecular Pharmacology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
Hermann-Kleiter
Natascha
N
Hinterleitner
Reinhard
R
Fresser
Friedrich
F
Schneider
Rainer
R
Gastl
Günther
G
Penninger
Josef M
JM
Baier
Gottfried
G
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D011493:Protein Kinase C / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000074121:Protein Kinase C-theta; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D054875:Ubiquitination / Q000235:genetics / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D018106:CD28 Antigens; C118387:Cblb protein, mouse; D007527:Isoenzymes; D011948:Receptors, Antigen, T-Cell; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta