Cutting edge: regulation of T cell activation threshold by CD28 costimulation through targeting Cbl-b for ubiquitination.
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.
Section of Molecular Medicine, Department of Orthopedic Surgery, Rush Medical College at Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL 60612, USA. jzhang1@rush.edu
Jian
J
Zhang
Tamás
T
Bárdos
Dongdong
D
Li
István
I
Gál
Csaba
C
Vermes
Jianye
J
Xu
Katalin
K
Mikecz
Alison
A
Finnegan
Stan
S
Lipkowitz
Tibor T
TT
Glant
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D018106:CD28 Antigens / Q000235:genetics / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism* / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D019169:Jurkat Cells; D008025:Ligases / Q000378:metabolism* / Q000502:physiology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010447:Peptide Hydrolases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism* / Q000502:physiology; D046988:Proteasome Endopeptidase Complex; D050721:Proto-Oncogene Proteins c-cbl; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
D048868:Adaptor Proteins, Signal Transducing; D018106:CD28 Antigens; D002352:Carrier Proteins; C118387:Cblb protein, mouse; D010750:Phosphoproteins; D025801:Ubiquitin; C492211:CBLB protein, human; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D008025:Ligases