IκB Kinase β Is Required for Activation of NF-κB and AP-1 in CD3/CD28-Stimulated Primary CD4+ T Cells

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-kappa B, 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-kappa B is dependent on protein kinase C theta, 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 IKK beta inhibitor PS-1145 or genetic ablation of IKK beta abrogates cell proliferation and impairs the activation of NF-kappa B 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 IKK beta activity promotes the time-dependent and cyclosporine-sensitive expression of negative regulators of T cell signaling leading to a hyporesponsive state of T cells. The Journal of Immunology, 2012, 188: 2545-2555.