title: Chronic activation of the kinase IKKβ impairs T cell function and survival.
abstract: Activation of the transcription factor NF-κB is critical for cytokine production and T cell survival after TCR engagement. The effects of persistent NF-κB 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-κB kinase β (caIKKβ) in a T cell-specific manner, we demonstrate that chronic inhibitor of NF-κB kinase β signaling promotes T cell apoptosis, attenuates responsiveness to TCR-mediated stimulation in vitro, and impairs T cell responses to bacterial infection in vivo. caIKKβ 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. caIKKβ 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 caIKKβ T cells to TCR triggering. Furthermore, adoptively transferred caIKKβ T cells showed diminished expansion and increased contraction in response to infection with Listeria monocytogenes expressing a cognate Ag. Despite their functional defects, caIKKβ T cells readily produced proinflammatory cytokines, and mice developed autoimmunity. In contrast to NF-κB's critical role in T cell activation and survival, our study demonstrates that persistent IKK-NF-κB signaling is sufficient to impair both T cell function and survival.
authors: Department of Pediatrics-Allergy and Immunology, Duke University Medical Center, Durham, NC 27710, USA.
authors: Sruti
authors: S
authors: Krishna
authors: Danli
authors: D
authors: Xie
authors: Balachandra
authors: B
authors: Gorentla
authors: Jinwook
authors: J
authors: Shin
authors: Jimin
authors: J
authors: Gao
authors: Xiao-Ping
authors: XP
authors: Zhong
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D002470:Cell Survival / Q000276:immunology*; D004195:Disease Models, Animal; D053222:Fas Ligand Protein / Q000096:biosynthesis; D051550:I-kappa B Kinase / Q000009:adverse effects* / Q000378:metabolism* / Q000502:physiology; D008088:Listeriosis / Q000201:enzymology / Q000276:immunology / Q000382:microbiology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000382:microbiology / Q000473:pathology*; D014157:Transcription Factors / Q000096:biosynthesis; D015854:Up-Regulation / Q000276:immunology
chemical_list: D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C513258:Prdm1 protein, mouse; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse