Abstract
Cbl-b negatively regulates CD28-dependent T cell activation. In this report, we tested the hypothesis that CD28 and CTLA-4 have opposite roles in tuning T cell activation threshold by controlling the levels of Cbl-b protein expression. We demonstrate that CD28 costimulation potentiates TCR-induced Cbl-b degradation, whereas CTLA-4-B7 interaction is required for Cbl-b re-expression. In support of this finding, Cbl-b expression in CTLA-4 knockout (KO) T cells is significantly reduced, and treating CTLA-4KO mice with human CTLA-4Ig to block CD28-B7 interaction restores Cbl-b expression on T cells. Furthermore, CD28 and CTLA-4 costimulatory effects are compromised in Cbl-bKO T cells. These observations indicate that CD28 and CTLA-4 tightly regulate Cbl-b expression which is critical for establishing the threshold for T cell activation.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Abatacept
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Adaptor Proteins, Signal Transducing / biosynthesis
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Adaptor Proteins, Signal Transducing / deficiency
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / physiology*
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Adjuvants, Immunologic / pharmacology
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Animals
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Antigens, CD
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Antigens, Differentiation / genetics
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Antigens, Differentiation / physiology*
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B7-1 Antigen / metabolism
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B7-1 Antigen / pharmacology
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CD28 Antigens / genetics
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CD28 Antigens / physiology*
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CTLA-4 Antigen
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Cell Proliferation
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Cells, Cultured
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Drug Synergism
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Female
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Growth Inhibitors / pharmacology
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Humans
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Immunoconjugates / pharmacology
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Lymphocyte Activation / genetics
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Lymphocyte Activation / immunology*
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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Proto-Oncogene Proteins c-cbl
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T-Lymphocyte Subsets / cytology
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T-Lymphocyte Subsets / immunology*
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T-Lymphocyte Subsets / metabolism
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Ubiquitin-Protein Ligases / biosynthesis
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Ubiquitin-Protein Ligases / deficiency
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / physiology*
Substances
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Adaptor Proteins, Signal Transducing
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Adjuvants, Immunologic
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Antigens, CD
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Antigens, Differentiation
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B7-1 Antigen
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CD28 Antigens
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CTLA-4 Antigen
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CTLA4 protein, human
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Cblb protein, mouse
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Ctla4 protein, mouse
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Growth Inhibitors
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Immunoconjugates
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Abatacept
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Proto-Oncogene Proteins c-cbl
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Ubiquitin-Protein Ligases