The kinase PDK1 integrates T cell antigen receptor and CD28 coreceptor signaling to induce NF-kappaB and activate T cells

Nat Immunol. 2009 Feb;10(2):158-66. doi: 10.1038/ni.1687. Epub 2009 Jan 4.

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

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3-Phosphoinositide-Dependent Protein Kinases
  • Animals
  • CARD Signaling Adaptor Proteins / immunology
  • CARD Signaling Adaptor Proteins / metabolism
  • CD28 Antigens / immunology*
  • CD28 Antigens / metabolism
  • Cell Survival
  • Electrophoretic Mobility Shift Assay
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Immunoprecipitation
  • Lymphocyte Activation / immunology*
  • Mice
  • Mice, Transgenic
  • Microscopy, Fluorescence
  • NF-kappa B / immunology*
  • NF-kappa B / metabolism
  • Phosphorylation
  • Protein Kinase C-delta / immunology
  • Protein Kinase C-delta / metabolism
  • Protein Serine-Threonine Kinases / metabolism*
  • Receptors, Antigen, T-Cell / immunology*
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction / immunology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism

Substances

  • CARD Signaling Adaptor Proteins
  • CD28 Antigens
  • Card11 protein, mouse
  • NF-kappa B
  • Receptors, Antigen, T-Cell
  • 3-Phosphoinositide-Dependent Protein Kinases
  • Pdpk1 protein, mouse
  • Protein Serine-Threonine Kinases
  • Protein Kinase C-delta