Abstract
Optimal T cell activation requires signaling through the TCR and CD28 costimulatory receptor. CD28 costimulation is believed to set the threshold for T cell activation. Recently, Cbl-b, a ubiquitin ligase, has been shown to negatively regulate CD28-dependent T cell activation. In this report, we show that CD28 costimulation selectively induces greater ubiquitination and degradation of Cbl-b in wild-type T cells than CD3 stimulation alone, and TCR-induced Cbl-b ubiquitination and degradation are significantly reduced in CD28-deficient T cells. Stimulation of CD28-deficient T cells with higher doses of anti-CD3 results in increased ubiquitination of Cbl-b, which correlates with enhanced T cell responses. Our results demonstrate that CD28 costimulation regulates the threshold for T cell activation, at least in part, by promoting Cbl-b ubiquitination and degradation.
Publication types
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Adaptor Proteins, Signal Transducing*
-
Animals
-
CD28 Antigens / genetics
-
CD28 Antigens / physiology*
-
Carrier Proteins / metabolism*
-
Carrier Proteins / physiology
-
Cells, Cultured
-
Female
-
Humans
-
Jurkat Cells
-
Ligases / metabolism*
-
Ligases / physiology
-
Lymphocyte Activation / immunology*
-
Mice
-
Mice, Inbred BALB C
-
Mice, Knockout
-
Peptide Hydrolases / metabolism
-
Phosphoproteins / metabolism*
-
Phosphoproteins / physiology
-
Proteasome Endopeptidase Complex*
-
Proto-Oncogene Proteins c-cbl
-
T-Lymphocytes / enzymology
-
T-Lymphocytes / immunology*
-
T-Lymphocytes / metabolism
-
Ubiquitin / metabolism*
-
Ubiquitin-Protein Ligases
Substances
-
Adaptor Proteins, Signal Transducing
-
CD28 Antigens
-
Carrier Proteins
-
Cblb protein, mouse
-
Phosphoproteins
-
Ubiquitin
-
CBLB protein, human
-
Proto-Oncogene Proteins c-cbl
-
Ubiquitin-Protein Ligases
-
Peptide Hydrolases
-
Proteasome Endopeptidase Complex
-
ATP dependent 26S protease
-
Ligases