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

Furmanski, AL; Barbarulo, A; Solanki, A; Lau, CI; Sahni, H; Saldana, JI; D'Acquisto, F; (2015) The transcriptional activator Gli2 modulates T-cell receptor signalling through attenuation of AP-1 and NFκ-B activity. J Cell Sci , 128 pp. 2085-2095. 10.1242/jcs.165803. Green open access

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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, via 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 (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 calcium flux and nuclear expression of NFAT, suppressed upregulation of molecules essential for activation, and attenuated signalling pathways upstream of AP-1 and NFκB, leading to reduced activation of these important transcription factors. Inhibition of physiological Hh-dependent transcription increased NFκB activity on TCR ligation. These data have importance for understanding 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, or in tumour microenvironments.

Type: Article
Title: The transcriptional activator Gli2 modulates T-cell receptor signalling through attenuation of AP-1 and NFκ-B activity.
Open access status: An open access version is available from UCL Discovery
DOI: 10.1242/jcs.165803
Publisher version: http://dx.doi.org/10.1242/jcs.165803
Additional information: © 2015. Published by The Company of Biologists Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/1468477
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