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

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 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.

The IFITM protein family in adaptive immunity

“…A third possibility is that the IFITM proteins are involved in enhancing or regulating the transduction of other signalling pathways that regulate Th differentiation. In support of this, they are transcriptional targets of Wnt and Hh signalling, 10,11 and both these pathways promote Th2 differentiation. 72,74,85,86 Finally, it is possible that the IFITM proteins have unknown direct consequences for Th differentiation through an influence on transcription or translation (as has been described for some viral genes).…”

“…Gene and protein expression studies have demonstrated that IFITM1-3 are expressed in murine CD4 + and CD8 + T cells. 7,11,13,37 Expression of Ifitm2 and Ifitm3 are regulated by TCR signalling. 13 In naive CD4 + T cells, RNA sequencing showed that expression of Ifitm3 was rapidly down-regulated during the first 24 hr after activation by anti-CD3/CD28 ligation in T helper type 0 (Th0), Th1 and Th2 culture conditions, whereas Ifitm2 was up-regulated and its expression continued to rise for the first 3 days after activation and levels of Ifitm1 were low and were not changed by TCR signalling.…”

“…70,71 Given the link between IFITM and Hh signalling and the fact that Hh signalling has also been shown to promote Th2 differentiation and exacerbate allergic asthma, it will be important to investigate the interactions between IFITM proteins and the Hh pathway in allergic asthma. 11,[72][73][74][75][76][77] The IFITM proteins are associated with other atopic and inflammatory diseases. In atopic dermatitis patients, IFITM1-3 are up-regulated in lesional skin compared with non-lesional skin from the same individuals, although the functional consequences of their increased expression have not been investigated.…”

“…[4][5][6][7] However, IFITM expression can be regulated independently of interferon signalling. 7,8 Ifitm genes are targets of transcriptional repression by Bcl6, and have been shown to be targets of Wnt/b-catenin and Hedgehog (Hh) signal transduction [9][10][11][12] ; and in murine T cells IFITM2 and IFITM3 expression is regulated by T-cell receptor (TCR) signal transduction. 7,9,13 In humans, five IFITM genes have been identified, which are located on chromosome 11, whereas in mice there are seven Ifitm genes, six of which are located on chromosome 7, and one on chromosome 16 (illustrated in Fig.…”

IFITM proteins drive type 2 T helper cell differentiation and exacerbate allergic airway inflammation

“…Genome‐wide association studies (GWAS) have indicated that the Hedgehog (Hh) signaling pathway plays a role in allergic asthma and experimental mouse asthma studies have shown that increased Hh signaling to T cells and eosinophils exacerbates the disease . Consistent with the reduction in allergic airways disease observed in the IfitmF ‐deficient mice, both Ifitm2 and Ifitm3 are Hh‐target genes in CD4 + T cells . In the future, it will be interesting to dissect the interactions between Hh pathway activation and IFITM function in asthma.…”