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

Sruti Krishna, Danli Xie, Balachandra Gorentla, Jinwook Shin, Jimin Gao and Xiao-Ping Zhong
J Immunol August 1, 2012, 189 (3) 1209-1219; DOI: https://doi.org/10.4049/jimmunol.1102429
Sruti Krishna
*Department of Pediatrics-Allergy and Immunology, Duke University Medical Center, Durham, NC 27710;
†Department of Immunology, Duke University Medical Center, Durham, NC 27710; and
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Danli Xie
*Department of Pediatrics-Allergy and Immunology, Duke University Medical Center, Durham, NC 27710;
‡School of Laboratory Medicine, Wenzhou Medical College, Wenzhou, Zhejiang Province 325035, China
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Balachandra Gorentla
*Department of Pediatrics-Allergy and Immunology, Duke University Medical Center, Durham, NC 27710;
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Jinwook Shin
*Department of Pediatrics-Allergy and Immunology, Duke University Medical Center, Durham, NC 27710;
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Jimin Gao
‡School of Laboratory Medicine, Wenzhou Medical College, Wenzhou, Zhejiang Province 325035, China
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Xiao-Ping Zhong
*Department of Pediatrics-Allergy and Immunology, Duke University Medical Center, Durham, NC 27710;
†Department of Immunology, Duke University Medical Center, Durham, NC 27710; and
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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.
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The Journal of Immunology: 189 (3)
The Journal of Immunology
Vol. 189, Issue 3
1 Aug 2012
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Chronic Activation of the Kinase IKKβ Impairs T Cell Function and Survival
Sruti Krishna, Danli Xie, Balachandra Gorentla, Jinwook Shin, Jimin Gao, Xiao-Ping Zhong
The Journal of Immunology August 1, 2012, 189 (3) 1209-1219; DOI: 10.4049/jimmunol.1102429

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Chronic Activation of the Kinase IKKβ Impairs T Cell Function and Survival
Sruti Krishna, Danli Xie, Balachandra Gorentla, Jinwook Shin, Jimin Gao, Xiao-Ping Zhong
The Journal of Immunology August 1, 2012, 189 (3) 1209-1219; DOI: 10.4049/jimmunol.1102429
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