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Cutting Edge |
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* Section of Molecular Medicine, Department of Orthopedic Surgery, and Departments of
Internal Medicine,
Biochemistry, and
Immunology/Microbiology, Rush Medical College at Rush-Presbyterian-St. Luke’s Medical Center, Chicago, IL 60612; and
¶ Genetics Department, Medicine Branch, National Cancer Institute, Bethesda, MD 20889
activated protein kinase; SHP-1, SH2 domain-bearing protein tyrosine phosphatase-1; HA, hemagglutinin; RIPA, radioimmunoprecipitation assay.
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.
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