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.
Footnotes
S.K. designed and conducted experiments, analyzed data, and wrote the manuscript; D.X. and B.G. conducted experiments and analyzed data; J.S. provided essential reagents; J.G. designed and supervised the experiments; and X.-P.Z. supervised the project, designed the research, and wrote the manuscript.
This work was supported by the National Institutes of Health (Grants R01AI076357, R01AI079088, and R21AI079873) and by the American Cancer Society (to X.-P.Z.).
The online version of this article contains supplemental material.
Abbreviations used in this article:
- Bcl10
- B cell lymphoma 10
- Blimp1
- B lymphocyte-induced maturation protein 1
- caIKKβ
- constitutively active form of inhibitor of NF-κB kinase, subunit β
- CD4SP
- CD4 single positive
- CD8SP
- CD8 single positive
- FasL
- Fas ligand
- IKK
- inhibitor of NF-κB kinase
- KO
- knockout
- Lm-OVA
- Listeria monocytogenes expressing rOVA
- LN
- lymph node
- PKCθ
- protein kinase C θ
- qPCR
- quantitative PCR
- TEM
- T effector memory
- Treg
- regulatory T cell
- WT
- wild-type.
- Received August 22, 2011.
- Accepted May 24, 2012.
- Copyright © 2012 by The American Association of Immunologists, Inc.