title: IκB kinase β is required for activation of NF-κB and AP-1 in CD3/CD28-stimulated primary CD4(+) T cells.
abstract: Engagement of the TCR and CD28 coreceptor by their respective ligands activates signal transduction cascades that ultimately lead to the activation of the transcription factors NFAT, AP-1, and NF-κB, which are required for the expression of cytokines and T cell clonal expansion. Previous studies have demonstrated that in mature T cells, activation of AP-1 and NF-κB is dependent on protein kinase C θ, suggesting the existence of a common signaling pathway. In this study, we show that in human primary CD4(+) T cells, exposure to the cell-permeable IKKβ inhibitor PS-1145 or genetic ablation of IKKβ abrogates cell proliferation and impairs the activation of NF-κB and AP-1 transcription factors in response to engagement of CD3 and CD28 coreceptor. In addition, we show that stimulation of T cells in the absence of IKKβ activity promotes the time-dependent and cyclosporine-sensitive expression of negative regulators of T cell signaling leading to a hyporesponsive state of T cells.
authors.affiliation: Section of Biochemistry, Department of Medicine and Experimental Oncology, University of Turin, 10126 Turin, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Lupino
authors.forename: Cristina
authors.initials: C
authors.lastname: Ramondetti
authors.forename: Marco
authors.initials: M
authors.lastname: Piccinini
mesh_terms: D015153:Blotting, Western; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D002469:Cell Separation; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D006801:Humans; D051550:I-kappa B Kinase / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D016328:NF-kappa B / Q000276:immunology* / Q000378:metabolism; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000276:immunology* / Q000378:metabolism
chemical_list: D018106:CD28 Antigens; D017252:CD3 Complex; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D051550:I-kappa B Kinase; C496560:IKBKB protein, human