IκB Kinase ε Is an NFATc1 Kinase that Inhibits T Cell Immune Response

Cell Rep. 2016 Jul 12;16(2):405-418. doi: 10.1016/j.celrep.2016.05.083. Epub 2016 Jun 23.


Activation of nuclear factor of activated T cells (NFAT) is crucial for immune responses. IKKε is an IκB kinase (IKK)-related kinase, and the function of IKKε remains obscure in T cells, despite its abundant expression. We report that IKKε inhibits NFAT activation and T cell responses by promoting NFATc1 phosphorylation. During T cell activation, IKKε was transiently activated to phosphorylate NFATc1. Loss of IKKε elevated T cell antitumor and antiviral immunity and, therefore, reduced tumor development and persistent viral infection. IKKε was activated in CD8(+) T cells of mice bearing melanoma or persistently infected with a model herpesvirus. These results collectively show that IKKε promotes NFATc1 phosphorylation and inhibits T cell responses, identifying IKKε as a crucial negative regulator of T cell activation and a potential target for immunotherapy.

MeSH terms

  • Adoptive Transfer
  • Animals
  • CD8-Positive T-Lymphocytes / enzymology
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Line, Tumor
  • Cricetinae
  • Herpesviridae Infections / enzymology
  • Herpesviridae Infections / immunology
  • I-kappa B Kinase / physiology*
  • Immunity, Cellular*
  • Lymphocyte Activation
  • Melanoma, Experimental / enzymology
  • Melanoma, Experimental / immunology
  • Mesocricetus
  • Mice, Knockout
  • NFATC Transcription Factors / metabolism*
  • Neoplasm Transplantation
  • Phosphorylation
  • Protein Processing, Post-Translational
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*
  • Virus Latency


  • NFATC Transcription Factors
  • Nfatc1 protein, mouse
  • I-kappa B Kinase
  • Ikbke protein, mouse