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

2.50
Hdl Handle:
http://hdl.handle.net/10547/576908
Title:
The transcriptional activator Gli2 modulates T-cell receptor signalling through attenuation of AP-1 and NFκB activity
Authors:
Furmanski, Anna L.; Barbarulo, Alessandro; Solanki, Anisha; Lau, Ching-In; Sahini, Hemant; Saldana, Jose Ignacio; D’Acquisto, Fulvio; Crompton, Tessa ( 0000-0002-8973-4021 )
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 Ca2+ 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 nderstanding 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.
Affiliation:
University College London; QMUL; University of Bedfordshire
Citation:
Furmanski AL, Barbarulo A, Solanki A, Lau CI, Sahni H, Saldana JI, D’Acquisto F & Crompton T, (2015) 'The transcriptional activator Gli2 modulates T-cell receptor signalling through attenuation of AP-1 and NFκ-B activity', Journal of Cell Science. Vol 128, pp 2085-2095
Publisher:
The Company of Biologists Ltd
Journal:
Journal of Cell Science
Issue Date:
2015
URI:
http://hdl.handle.net/10547/576908
DOI:
10.1242/​jcs.165803
PubMed ID:
25908851
PubMed Central ID:
PMC4450292
Additional Links:
http://jcs.biologists.org/content/128/11/2085.full.pdf+html?with-ds=yes
Type:
Article
Language:
en
ISSN:
1477-9137; 0021-9533
Sponsors:
Biotechnology and Biological Sciences Research Council (BBSRC) [grant number BBSRC BB/I026324/1]; and the UK Medical Research Council (MRC) [grant number MRC G0900161]. A.L.F is supported by Asthma UK [grant number AUK-SPD-2012- 171]. H.S. was supported by a Child Health Research (CHR) studentship, A.B. by Istituto Pasteur/Cenci Bolognetti and A.S and T.C by Great Ormond Street Children's Charity (GOSHCC). Deposited in PMC for immediate release.
Appears in Collections:
Biomedical Science

Full metadata record

DC FieldValue Language
dc.contributor.authorFurmanski, Anna L.en
dc.contributor.authorBarbarulo, Alessandroen
dc.contributor.authorSolanki, Anishaen
dc.contributor.authorLau, Ching-Inen
dc.contributor.authorSahini, Hemanten
dc.contributor.authorSaldana, Jose Ignacioen
dc.contributor.authorD’Acquisto, Fulvioen
dc.contributor.authorCrompton, Tessaen
dc.date.accessioned2015-09-07T13:22:23Zen
dc.date.available2015-09-07T13:22:23Zen
dc.date.issued2015en
dc.identifier.citationFurmanski AL, Barbarulo A, Solanki A, Lau CI, Sahni H, Saldana JI, D’Acquisto F & Crompton T, (2015) 'The transcriptional activator Gli2 modulates T-cell receptor signalling through attenuation of AP-1 and NFκ-B activity', Journal of Cell Science. Vol 128, pp 2085-2095en
dc.identifier.issn1477-9137en
dc.identifier.issn0021-9533en
dc.identifier.pmid25908851en
dc.identifier.doi10.1242/​jcs.165803en
dc.identifier.urihttp://hdl.handle.net/10547/576908en
dc.description.abstractDifferent 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 Ca2+ 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 nderstanding 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.en
dc.description.sponsorshipBiotechnology and Biological Sciences Research Council (BBSRC) [grant number BBSRC BB/I026324/1]; and the UK Medical Research Council (MRC) [grant number MRC G0900161]. A.L.F is supported by Asthma UK [grant number AUK-SPD-2012- 171]. H.S. was supported by a Child Health Research (CHR) studentship, A.B. by Istituto Pasteur/Cenci Bolognetti and A.S and T.C by Great Ormond Street Children's Charity (GOSHCC). Deposited in PMC for immediate release.en
dc.language.isoenen
dc.publisherThe Company of Biologists Ltden
dc.relation.urlhttp://jcs.biologists.org/content/128/11/2085.full.pdf+html?with-ds=yesen
dc.subjectHedgehogen
dc.subjectGli2en
dc.subjectT-cellen
dc.subjectTCRen
dc.subjectAP-1en
dc.subjectNFκBen
dc.subjectIL-2en
dc.subjecttranscriptionen
dc.subjectcell scienceen
dc.subjectC130 Cell Biologyen
dc.titleThe transcriptional activator Gli2 modulates T-cell receptor signalling through attenuation of AP-1 and NFκB activityen
dc.typeArticleen
dc.contributor.departmentUniversity College Londonen
dc.contributor.departmentQMULen
dc.contributor.departmentUniversity of Bedfordshireen
dc.identifier.journalJournal of Cell Scienceen
dc.identifier.pmcidPMC4450292en

Related articles on PubMed

This item is licensed under a Creative Commons License
Creative Commons
All Items in UOBREP are protected by copyright, with all rights reserved, unless otherwise indicated.