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

J Immunol. 2012 Aug 1;189(3):1209-19. doi: 10.4049/jimmunol.1102429. Epub 2012 Jun 29.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / immunology
  • Cell Survival / immunology*
  • Disease Models, Animal
  • Fas Ligand Protein / biosynthesis
  • I-kappa B Kinase / adverse effects*
  • I-kappa B Kinase / metabolism*
  • I-kappa B Kinase / physiology
  • Listeriosis / enzymology
  • Listeriosis / immunology
  • Listeriosis / microbiology
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Positive Regulatory Domain I-Binding Factor 1
  • Receptors, Antigen, T-Cell / metabolism
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / microbiology
  • T-Lymphocyte Subsets / pathology*
  • Transcription Factors / biosynthesis
  • Up-Regulation / immunology

Substances

  • Fas Ligand Protein
  • Fasl protein, mouse
  • Prdm1 protein, mouse
  • Receptors, Antigen, T-Cell
  • Transcription Factors
  • Positive Regulatory Domain I-Binding Factor 1
  • I-kappa B Kinase
  • Ikbkb protein, mouse