| First Author | Krishna S | Year | 2012 |
| Journal | J Immunol | Volume | 189 |
| Issue | 3 | Pages | 1209-19 |
| PubMed ID | 22753932 | Mgi Jnum | J:189775 |
| Mgi Id | MGI:5446981 | Doi | 10.4049/jimmunol.1102429 |
| Citation | Krishna S, et al. (2012) Chronic activation of the kinase IKKbeta impairs T cell function and survival. J Immunol 189(3):1209-19 |
| abstractText | Activation of the transcription factor NF-kappaB is critical for cytokine production and T cell survival after TCR engagement. The effects of persistent NF-kappaB 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-kappaB kinase beta (caIKKbeta) in a T cell-specific manner, we demonstrate that chronic inhibitor of NF-kappaB 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. caIKKbeta 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. caIKKbeta 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 caIKKbeta T cells to TCR triggering. Furthermore, adoptively transferred caIKKbeta T cells showed diminished expansion and increased contraction in response to infection with Listeria monocytogenes expressing a cognate Ag. Despite their functional defects, caIKKbeta T cells readily produced proinflammatory cytokines, and mice developed autoimmunity. In contrast to NF-kappaB's critical role in T cell activation and survival, our study demonstrates that persistent IKK-NF-kappaB signaling is sufficient to impair both T cell function and survival. |
