It takes a village: STATs control IE-CTL pathogenesis in Celiac Disease

Abstract

Abstract Celiac Disease (CeD) is an autoimmune-like inflammatory disorder triggered by exposure to dietary gluten in genetically predisposed individuals. Tissue destruction in CeD is driven by tissue-resident, cytotoxic CD8+ intraepithelial lymphocytes (IE-CTLs). Upregulation of tissue alarmins and inflammatory cytokines – including IL-15, IL-21, and type I interferon – is evident in biopsies from CeD patients. It is thought that these cytokines may license IE-CTLs to kill stressed intestinal epithelial cells and contribute to their long-term pathogenic reprogramming. We therefore explored the contribution of these cytokines, interferons, and TCR stimulation in IE-CTL activation and pathogenic conversion. We found that both cytokine and TCR stimulation induced overlapping and distinct transcriptional programs. Pathways associated with activation and effector function were most robustly induced by a combination of cytokines. Further, genes identified from CeD-associated GWAS were also more strongly induced by cytokine stimulation. Cytokine signaling resulted in the activation of signal transducer and activator of transcription (STAT) pathways, which subsequently act as key TFs in IE-CTL reprogramming. To link specific transcriptional responses to particular STATs we performed individual and combined knockdowns of the four STATs associated with these cytokines. Our results showed significant redundancy in the STAT signaling pathways following cytokine stimulation, suggesting that convergence in individual STAT signaling nodes in IE-CTLs is integral to CeD pathogenesis. Supported by grants from NSF GRFP 1746045 and NIH BIBIB 2 T32 EB 9412.