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Chronic activation of the kinase IKKβ impairs T cell function and survival.

Publication ,  Journal Article
Krishna, S; Xie, D; Gorentla, B; Shin, J; Gao, J; Zhong, X-P
Published in: J Immunol
August 1, 2012

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.

Duke Scholars

Published In

J Immunol

DOI

EISSN

1550-6606

Publication Date

August 1, 2012

Volume

189

Issue

3

Start / End Page

1209 / 1219

Location

United States

Related Subject Headings

  • Up-Regulation
  • Transcription Factors
  • T-Lymphocyte Subsets
  • Receptors, Antigen, T-Cell
  • Positive Regulatory Domain I-Binding Factor 1
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice
  • Lymphocyte Activation
  • Listeriosis
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Krishna, S., Xie, D., Gorentla, B., Shin, J., Gao, J., & Zhong, X.-P. (2012). Chronic activation of the kinase IKKβ impairs T cell function and survival. J Immunol, 189(3), 1209–1219. https://doi.org/10.4049/jimmunol.1102429
Krishna, Sruti, Danli Xie, Balachandra Gorentla, Jinwook Shin, Jimin Gao, and Xiao-Ping Zhong. “Chronic activation of the kinase IKKβ impairs T cell function and survival.J Immunol 189, no. 3 (August 1, 2012): 1209–19. https://doi.org/10.4049/jimmunol.1102429.
Krishna S, Xie D, Gorentla B, Shin J, Gao J, Zhong X-P. Chronic activation of the kinase IKKβ impairs T cell function and survival. J Immunol. 2012 Aug 1;189(3):1209–19.
Krishna, Sruti, et al. “Chronic activation of the kinase IKKβ impairs T cell function and survival.J Immunol, vol. 189, no. 3, Aug. 2012, pp. 1209–19. Pubmed, doi:10.4049/jimmunol.1102429.
Krishna S, Xie D, Gorentla B, Shin J, Gao J, Zhong X-P. Chronic activation of the kinase IKKβ impairs T cell function and survival. J Immunol. 2012 Aug 1;189(3):1209–1219.

Published In

J Immunol

DOI

EISSN

1550-6606

Publication Date

August 1, 2012

Volume

189

Issue

3

Start / End Page

1209 / 1219

Location

United States

Related Subject Headings

  • Up-Regulation
  • Transcription Factors
  • T-Lymphocyte Subsets
  • Receptors, Antigen, T-Cell
  • Positive Regulatory Domain I-Binding Factor 1
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice
  • Lymphocyte Activation
  • Listeriosis