The kinase PDK1 integrates T cell antigen receptor and CD28 coreceptor signaling to induce NF-kappaB and activate T cells.
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.
Park
Sung-Gyoo
SG
Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Schulze-Luehrman
Jan
J
Hayden
Matthew S
MS
Hashimoto
Naoko
N
Ogawa
Wataru
W
Kasuga
Masato
M
Ghosh
Sankar
S
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D053468:CARD Signaling Adaptor Proteins / Q000276:immunology / Q000378:metabolism; D018106:CD28 Antigens / Q000276:immunology* / Q000378:metabolism; D002470:Cell Survival; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D047468:Immunoprecipitation; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D016328:NF-kappa B / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000276:immunology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D053468:CARD Signaling Adaptor Proteins; D018106:CD28 Antigens; C496467:Card11 protein, mouse; D016328:NF-kappa B; D011948:Receptors, Antigen, T-Cell; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578564:Pdpk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051745:Protein Kinase C-delta