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

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