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.

IκB kinase β is required for activation of NF-κB and AP-1 in CD3/CD28-stimulated primary CD4(+) T cells.

LUPINO, Elisa;RAMONDETTI, Cristina;PICCININI, Marco
2012-01-01

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.
188
2545
2555
http://www.jimmunol.org/content/188/6/2545.long
T-cell activation NF-kappaB AP1 Immune tolerance
Lupino E; Ramondetti C; Piccinini M.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/138019
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