Systems analysis of human Thelper17 cell differentiation uncovers distinct time-regulated transcriptional modules

Abstract Th17 cells protect from infections and are pathogenic in autoimmunity. While human Th17 cell differentiation has been defined, the global and stepwise transcriptional changes accompanying this process remain uncharacterized. Herein, by performing transcriptome analysis of human Th17 cells we uncovered three time-regulated modules: early, involving exclusively ‘signalling pathways’ genes; late, characterized by response to infections; persistent, involving effector immune functions. To assign them an inflammatory or regulatory potential, we compared Th17 cells differentiated in presence or absence of IL-1β, respectively. Most inflammatory genes belong to the persistent module, while regulatory genes are lately or persistently induced. Among inflammatory genes, we identified the effector molecules IL17A, IL17F, IL26, IL6, IFNG, IFNK, LTA, IL1A, PDGFA, and the transcriptional regulators HOPX, SOX2, whose expression was independently validated. This study represents an integrative analysis of the stepwise human Th17 differentiation program and offers new perspectives towards therapeutic targeting of Th17-related autoimmune diseases.