The transcriptional activator Gli2 modulates T-cell receptor signalling through attenuation of AP-1 and NFκB activity
AuthorsFurmanski, Anna L.
Saldaña, José Ignacio
MetadataShow full item record
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.
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 2085-2095
PublisherThe Company of Biologists Ltd
JournalJournal of Cell Science
PubMed Central IDPMC4450292
SponsorsBiotechnology 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.
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