I KAPPA B KINASE (IKK)-EPSILON TARGETS INTERFERON REGULATORY FACTOR 1 IN ACTIVATED T LYMPHOCYTES. The I-kappa-B kinase epsilon (IKK-ε) has an essential role as a regulator of innate immunity, functioning downstream of pattern recognition receptors to modulate NF-κB and interferon (IFN) signaling. In the present study, we investigated IKKε activation following T cell receptor (TCR)/CD28 stimulation of primary CD4(+) T cells and its role in the stimulation of a type I IFN response. IKK-ε was activated following TCR/CD28 stimulation of primary CD4(+) T cells; however, in T cells treated with poly I:C, TCR/CD28 co-stimulation blocked induction of IFN-β transcription. We demonstrated that IKK-ε phosphorylated transcription factor IRF1 at residues aa215/219/221 in primary CD4(+) T cells and blocked its transcriptional activity. At the mechanistic level, IRF-1 phosphorylation impaired the physical interaction between IRF-1 and the NF-κB RelA subunit, and interfered with PCAF-mediated acetylation of NF-κB RelA. These results demonstrate that TCR/CD28 stimulation of primary T cells stimulates IKKε activation, which in turns contributes to suppression of IFNβ production. 