Abstract
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 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.
Highlights
Peripheral T-cell activation, differentiation and clonal expansion are controlled by complex signals, which are initiated by interaction of the T-cell receptor (TCR) with its major histocompatibility complex (MHC)–peptide ligand
Gli transcription factors are expressed in WT T-cells To show that WT T-cells express the essential Hh-responsive transcription factor Gli2, we investigated Gli2 protein expression and localisation by western blotting extracts from CD4+ cells purified from spleen (Fig. 1A)
Here, we showed that Gli2 transcriptional activator isoform (Gli2A)-mediated transcription in T-cells attenuated T-cell signalling and T-cell activation on CD3/CD28 ligation
Summary
Peripheral T-cell activation, differentiation and clonal expansion are controlled by complex signals, which are initiated by interaction of the T-cell receptor (TCR) with its major histocompatibility complex (MHC)–peptide ligand. Received 7 November 2014; Accepted 30 March 2015 transcriptional response to TCR signalling controls the subsequent activation and resolution of the adaptive immune response (Thompson et al, 1989; Smith-Garvin et al, 2009; Cheng et al, 2011). Activation of T-cells induces synthesis of IL-2 and upregulation of cell surface CD25 (IL-2Rα), the high-affinity IL-2 receptor subunit, providing a feedback loop that enhances IL-2 signalling. Persistent stimulation of T-cells through TCR and IL-2 signalling eventually induces apoptotic pathways, resulting in activation-induced cell death (AICD). The influence of non-immune tissue-derived molecules on T-cell activation requires investigation
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