Dynamic and distinct transcriptional response of CD8+ cytotoxic T lymphocytes to tissue alarmins and adaptive cytokines

The respective effects of tissue alarmins like interleukin (IL)-15 and interferon beta (IFNb), and cytokines like IL-21 on the intraepithelial cytotoxic T lymphocytes (IE-CTLs) that cause autoimmune-mediated tissue destruction, is poorly understood. Analysis of the dynamics of transcriptomic and epigenomic profiles in primary IE-CTLs showed massive and distinct temporal transcriptional changes upon induction by tissue alarmins IL-15 and IFNb, while the impact of IL-21 was limited. Only anti-viral pathways were induced in response to all the three stimuli. Interestingly, the dynamically differentially expressed genes (DEGs), in particular genes in involved in IFN pathways, are enriched in autoimmune diseases risk loci. Changes in gene expression were primarily independent of changes in H3K27ac, but were enriched in differentially expressed non-coding (nc) RNAs. Together these results provide new insights into molecular mechanisms that fuel the activation of tissue resident CTLs under conditions that mimic aspects of the inflammatory environment in patients with immune-mediated diseases Overall design: RNASeq of IE-CTLs upon IFNb, IL15 and IL21 stimulations at 3h, 4h and 24h