Systems analysis of human T helper17 cell differentiation uncovers distinct time-regulated transcriptional modules

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. This study represents the first integrative analysis of the stepwise human Th17 differentiation program and offers new perspectives towards therapeutic targeting of Th17-related autoimmune diseases. Total RNA-sequencing analyses of naïve CD4+ T cells, either unpolarised (Th0) or differentiated under "inflammatory"(Th17) or "regulatory" (Th17 without IL1b) Th17 conditions, obtained from 5 independent healthy donors (HD), harvested at 48h and 5 days of differentiation.