Journal
JOURNAL OF CELL SCIENCE
Volume 128, Issue 11, Pages 2085-2095Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.165803
Keywords
Hedgehog; Gli2; T-cell; TCR; AP-1; NF kappa B; IL-2
Categories
Funding
- Wellcome Trust [WT094255MF]
- Biotechnology and Biological Sciences Research Council (BBSRC) [BBSRC BB/I026324/1]
- UK Medical Research Council (MRC) [MRC G0900161]
- Asthma UK [AUK-SPD-2012-171]
- Child Health Research (CHR) studentship
- Istituto Pasteur/Cenci Bolognetti
- Great Ormond Street Children's Charity (GOSHCC)
- Biotechnology and Biological Sciences Research Council [BB/H005188/1, BB/I026324/1] Funding Source: researchfish
- Great Ormond Street Hospital Childrens Charity [V1297] Funding Source: researchfish
- Medical Research Council [G0900161, 1342014, 1212180] Funding Source: researchfish
- BBSRC [BB/H005188/1, BB/I026324/1] Funding Source: UKRI
- MRC [G0900161] Funding Source: UKRI
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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 NF kappa B complexes, leading to reduced activation of these important transcription factors. Inhibition of physiological Hh-dependent transcription increased NF kappa B 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 TGF beta are upregulated, including during inflammation, tissue damage and repair, and in tumour microenvironments.
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