Chronic Activation of the Kinase IKKβ Impairs T Cell Function and Survival

Activation of the transcription factor NF-kappa B is critical for cytokine production and T cell survival after TCR engagement. The effects of persistent NF-kappa B activity on T cell function and survival are poorly understood. In this study, using a murine model that expresses a constitutively active form of inhibitor of NF-kappa B kinase beta (caIKK beta) in a T cell-specific manner, we demonstrate that chronic inhibitor of NF-kappa B kinase beta signaling promotes T cell apoptosis, attenuates responsiveness to TCR-mediated stimulation in vitro, and impairs T cell responses to bacterial infection in vivo. caIKK beta T cells showed increased Fas ligand expression and caspase-8 activation, and blocking Fas/Fas ligand interactions enhanced cell survival. T cell unresponsiveness was associated with defects in TCR proximal signaling and elevated levels of B lymphocyte-induced maturation protein 1, a transcriptional repressor that promotes T cell exhaustion. caIKK beta T cells also showed a defect in IL-2 production, and addition of exogenous IL-2 enhanced their survival and proliferation. Conditional deletion of B lymphocyte-induced maturation protein 1 partially rescued the sensitivity of caIKK beta T cells to TCR triggering. Furthermore, adoptively transferred caIKK beta T cells showed diminished expansion and increased contraction in response to infection with Listeria monocytogenes expressing a cognate Ag. Despite their functional defects, caIKK beta T cells readily produced proinflammatory cytokines, and mice developed autoimmunity. In contrast to NF-kappa B's critical role in T cell activation and survival, our study demonstrates that persistent IKK-NF-kappa B signaling is sufficient to impair both T cell function and survival. The Journal of Immunology, 2012, 189: 1209-1219.