Abstract
Stimulation of T cells via the antigen and costimulatory receptors leads to the organization of a supramolecular activation cluster called the immune synapse. We report that loss of the molecular adaptor Cbl-b in T cells frees antigen receptor-triggered receptor clustering, lipid raft aggregation, and sustained tyrosine phosphorylation from the requirement for CD28 costimulation. Introduction of the cbl-b mutation into a vav1-/- background relieved the functional defects of vav1-/- T cells and caused spontaneous autoimmunity. Wiscott Aldrich Syndrome protein (WASP) was found to be essential for deregulated proliferation and membrane receptor reorganization of cbl-b mutant T cells. Antigen receptor-triggered Ca2+ mobilization, cytokine production, and receptor clustering can be genetically uncoupled in cbl-b mutant T cells. Thus, Cbl-b functions as a negative regulator of receptor clustering and raft aggregation in T cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Animals
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Autoimmune Diseases / genetics
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Calcium Signaling / genetics
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Calcium Signaling / immunology
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Carrier Proteins / genetics
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Carrier Proteins / physiology*
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Cell Cycle Proteins*
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Cytotoxicity, Immunologic / genetics
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Down-Regulation / genetics
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Down-Regulation / immunology*
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Enzyme Activation / genetics
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Enzyme Activation / immunology
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Genetic Complementation Test
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Humans
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Interleukin-2 / biosynthesis
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Lymphocyte Activation / genetics
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Lymphoproliferative Disorders / genetics
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Membrane Microdomains / genetics
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Membrane Microdomains / immunology*
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Membrane Microdomains / metabolism*
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Mice
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Mice, Knockout
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NFATC Transcription Factors
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Nuclear Proteins*
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Phosphoproteins / deficiency
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Phosphoproteins / genetics
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Phosphoproteins / physiology*
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Phosphorylation
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Proteins / genetics
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Proteins / physiology
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Proto-Oncogene Proteins / deficiency
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / physiology
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Proto-Oncogene Proteins c-cbl
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Proto-Oncogene Proteins c-vav
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Receptor Aggregation / genetics
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Receptor Aggregation / immunology*
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Receptors, Antigen, T-Cell / metabolism
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Receptors, Antigen, T-Cell / physiology
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T-Lymphocytes / enzymology
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism*
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T-Lymphocytes, Cytotoxic / immunology
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T-Lymphocytes, Cytotoxic / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcriptional Activation / immunology
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Tyrosine / metabolism
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Ubiquitin-Protein Ligases*
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Wiskott-Aldrich Syndrome / genetics
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Wiskott-Aldrich Syndrome / immunology
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Wiskott-Aldrich Syndrome Protein
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cdc42 GTP-Binding Protein / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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Cblb protein, mouse
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Cell Cycle Proteins
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DNA-Binding Proteins
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Interleukin-2
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NFATC Transcription Factors
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Nuclear Proteins
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Phosphoproteins
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Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-vav
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Receptors, Antigen, T-Cell
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Transcription Factors
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VAV1 protein, human
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Vav1 protein, mouse
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WAS protein, human
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Was protein, mouse
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Wiskott-Aldrich Syndrome Protein
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Tyrosine
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CBLB protein, human
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Proto-Oncogene Proteins c-cbl
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Ubiquitin-Protein Ligases
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cdc42 GTP-Binding Protein