Costimulation Reverses the Defect in IL-2 But Not Effector Cytokine Production by T Cells with Impaired IκBα Degradation

Abstract

Abstract Although the transcriptional basis for states of unresponsiveness in primary T cells is unclear, tolerant B lymphocytes exhibit inhibition of both c-Jun N-terminal kinase induction and IκBα (inhibitor of NF-κBα) degradation, leading to lower levels of both nuclear AP-1 and NF-κB. Expression of an IκBα mutant resistant to signal-induced degradation in transgenic T cells caused markedly deficient effector cytokine (IL-4, IFN-γ) production after primary TCR stimulation despite a detectable level of nuclear NF-κB. A TCR response element from the IFN-γ promoter, despite lacking detectable NF-κB/Rel sites, was also unresponsive to TCR ligation. Nuclear induction of AP-1 proteins in response to T cell activation was diminished in transgenic T cells. Costimulation induced by anti-CD28 mAb increased IL-2 production, but failed to reverse the defects in effector cytokine production. Taken together, these data indicate that impaired NF-κB/Rel signaling in T cells interferes with the signal transduction pathways required for efficient induction of effector cytokine production.