Abstract
In addition to ligation of the T cell antigen receptor (TCR), activation of the CD28 coreceptor by the costimulatory molecule B7 is required for induction of the transcription factor NF-kappaB and robust T cell activation, although the contribution of CD28 to this process remains incompletely understood. We show here that phosphoinositide-dependent kinase 1 (PDK1) is essential for integrating the TCR and CD28 signals. After we deleted PDK1 from T cells, TCR-CD28 signals were unable to induce activation of NF-kappaB or phosphorylation of protein kinase C-theta, although T cell survival and pathways dependent on the kinases p38 and Jnk or the transcription factor NFAT were unaffected. CD28 facilitated NF-kappaB activation by regulating recruitment and phosphorylation of PDK1, which are necessary for efficient binding of PDK1 to protein kinase C-theta and the adaptor CARMA1 and thus for NF-kappaB induction.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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3-Phosphoinositide-Dependent Protein Kinases
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Animals
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CARD Signaling Adaptor Proteins / immunology
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CARD Signaling Adaptor Proteins / metabolism
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CD28 Antigens / immunology*
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CD28 Antigens / metabolism
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Cell Survival
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Electrophoretic Mobility Shift Assay
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Enzyme-Linked Immunosorbent Assay
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Flow Cytometry
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Immunoprecipitation
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Lymphocyte Activation / immunology*
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Mice
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Mice, Transgenic
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Microscopy, Fluorescence
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NF-kappa B / immunology*
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NF-kappa B / metabolism
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Phosphorylation
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Protein Kinase C-delta / immunology
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Protein Kinase C-delta / metabolism
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Protein Serine-Threonine Kinases / metabolism*
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Receptors, Antigen, T-Cell / immunology*
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Receptors, Antigen, T-Cell / metabolism
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Signal Transduction / immunology
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T-Lymphocytes / immunology*
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T-Lymphocytes / metabolism
Substances
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CARD Signaling Adaptor Proteins
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CD28 Antigens
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Card11 protein, mouse
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NF-kappa B
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Receptors, Antigen, T-Cell
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3-Phosphoinositide-Dependent Protein Kinases
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Pdpk1 protein, mouse
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Protein Serine-Threonine Kinases
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Protein Kinase C-delta