The transcriptional activator Gli2 modulates T-cell receptor signalling through attenuation of AP-1 and NFκB activity

Anna L Furmanski, Alessandro Barbarulo, Anisha Solanki, Ching-In Lau, Hemant Sahni, Jose Ignacio Saldana, Fulvio D'Acquisto, Tessa Crompton

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Abstract

Different tissues contain diverse and dynamic cellular niches, providing distinct signals to tissue-resident or migratory infiltrating immune cells. Hedgehog (Hh) proteins are secreted inter-cellular signalling molecules, which are essential during development and are important in cancer, post-natal tissue homeostasis and repair. Hh signalling mediated by the Hh-responsive transcription factor Gli2 also has multiple roles in T-lymphocyte development and differentiation. Here, we investigate the function of Gli2 in T-cell signalling and activation. Gene transcription driven by the Gli2 transcriptional activator isoform (Gli2A) attenuated T-cell activation and proliferation following T-cell receptor (TCR) stimulation. Expression of Gli2A in T-cells altered gene expression profiles, impaired the TCR-induced Ca(2+) flux and nuclear expression of NFAT2, suppressed upregulation of molecules essential for activation, and attenuated signalling pathways upstream of the AP-1 and NFκB complexes, leading to reduced activation of these important transcription factors. Inhibition of physiological Hh-dependent transcription increased NFκB activity upon TCR ligation. These data are important for understanding the molecular mechanisms of immunomodulation, particularly in tissues where Hh proteins or other Gli-activating ligands such as TGFβ are upregulated, including during inflammation, tissue damage and repair, and in tumour microenvironments.


© 2015, The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See http://creativecommons.org/licenses/by/4.0/



Original languageEnglish
Pages (from-to)2085-95
Number of pages11
JournalJournal of Cell Science
Volume128
Issue number11
DOIs
Publication statusPublished - 1 Jun 2015

Keywords

  • Animals
  • Cell Differentiation
  • Cell Proliferation
  • Gene Expression Regulation
  • Hedgehog Proteins
  • Kruppel-Like Transcription Factors
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B
  • NFATC Transcription Factors
  • Receptors, Antigen, T-Cell
  • Signal Transduction
  • T-Lymphocytes
  • Transcription Factor AP-1
  • Transcriptional Activation
  • Transcriptome
  • Transforming Growth Factor beta
  • Up-Regulation
  • Zinc Finger Protein Gli2
  • Journal Article
  • Research Support, Non-U.S. Gov't

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