title: The transcriptional activator Gli2 modulates T-cell receptor signalling through attenuation of AP-1 and NFκB activity.
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.
authors.affiliation: Immunobiology Section, Institute of Child Health, University College London, London WC1N 1EH, UK anna.furmanski@beds.ac.uk.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Furmanski
authors.affiliation: Immunobiology Section, Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Barbarulo
authors.affiliation: Immunobiology Section, Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Anisha
authors.initials: A
authors.lastname: Solanki
authors.affiliation: Immunobiology Section, Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Ching-In
authors.initials: CI
authors.lastname: Lau
authors.affiliation: Immunobiology Section, Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Hemant
authors.initials: H
authors.lastname: Sahni
authors.affiliation: Immunobiology Section, Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Jose Ignacio
authors.initials: JI
authors.lastname: Saldana
authors.affiliation: Centre for Biochemical Pharmacology, William Harvey Research Institute, QMUL, London EC1M 6BQ, UK.
authors.forename: Fulvio
authors.initials: F
authors.lastname: D'Acquisto
authors.affiliation: Immunobiology Section, Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Tessa
authors.initials: T
authors.lastname: Crompton
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D053823:Hedgehog Proteins / Q000235:genetics; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics*; D050778:NFATC Transcription Factors / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D013601:T-Lymphocytes / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics; D000075746:Zinc Finger Protein Gli2
chemical_list: C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D016328:NF-kappa B; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D011948:Receptors, Antigen, T-Cell; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D000075746:Zinc Finger Protein Gli2
keywords: AP-1; Gli2; Hedgehog; IL-2; NFκB; T-cell; TCR