Abstract
Since CD28 provides cosignals in T cell responses, a key question is whether the coreceptor operates exclusively via TCRzeta/CD3 or also operates as an independent signaling unit. In this study, we show that CD28 can cooperate with VAV/SLP-76 adaptors to upregulate interleukin 2/4 transcription independently of TCR ligation. CD28 signaling is dependent on VAV/SLP-76 complex formation and induces membrane localization of these complexes. CD28-VAV/SLP-76 also functions in nonlymphoid cells to promote nuclear entry of NFAT, indicating that these adaptors are the only lymphoid components needed for this pathway. Further downstream, CD28-VAV/SLP-76 synergizes with Rac1 and causes F-actin remodelling proximal to receptor. Autonomous CD28 signaling may account for the distinct nature of the second signal and in trans amplification of T cell responses.
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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Actins / metabolism
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Adaptor Proteins, Signal Transducing
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Amino Acid Motifs
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Animals
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B7-1 Antigen / genetics
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B7-1 Antigen / immunology
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Biopolymers
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CD28 Antigens / physiology*
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CHO Cells
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COS Cells
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Cell Cycle Proteins*
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Cell Membrane / metabolism
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Chlorocebus aethiops
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Cricetinae
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Cricetulus
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DNA-Binding Proteins / metabolism
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Gene Expression Regulation / physiology*
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Humans
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Interleukin-2 / biosynthesis*
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Interleukin-2 / genetics
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Interleukin-4 / biosynthesis*
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Interleukin-4 / genetics
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Jurkat Cells / immunology
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Ligands
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Lymphocyte Activation / physiology*
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Macromolecular Substances
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NFATC Transcription Factors
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Nuclear Proteins*
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Phosphoproteins / chemistry
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Phosphoproteins / physiology*
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Protein Binding
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Proto-Oncogene Proteins / chemistry
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Proto-Oncogene Proteins / physiology*
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Proto-Oncogene Proteins c-vav
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Receptors, Antigen, T-Cell / immunology*
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Recombinant Fusion Proteins / physiology
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Signal Transduction / physiology*
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T-Lymphocytes / immunology*
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Transcription Factors / metabolism
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Transcription, Genetic / physiology*
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rac1 GTP-Binding Protein / physiology
Substances
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Actins
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Adaptor Proteins, Signal Transducing
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B7-1 Antigen
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Biopolymers
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CD28 Antigens
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Cell Cycle Proteins
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DNA-Binding Proteins
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Interleukin-2
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Ligands
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Macromolecular Substances
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NFATC Transcription Factors
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Nuclear Proteins
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Phosphoproteins
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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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Recombinant Fusion Proteins
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SLP-76 signal Transducing adaptor proteins
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Transcription Factors
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VAV1 protein, human
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Interleukin-4
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rac1 GTP-Binding Protein