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

T helper (Th) 17 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 signaling pathways'' genes; late, characterized by response to infections; and persistent, involving effector immune functions. To assign them an inflammatory or regulatory potential, we compared Th17 cells differentiated in presence or absence of interleukin (IL)-1 beta, respectively. Most inflammatory genes belong to the persistent module, whereas regulatory genes are lately or persistently induced. Among inflammatory genes, we identified the effector molecules IL17A, IL17F, IL26, IL6, interferon (IFN)G, IFNK, LTA, IL1A, platelet-derived growth factor (PDGF) A and the transcriptional regulators homeodomain-only protein homeobox (HOPX) and sex-determining-region-Y-box (SOX)2, whose expression was independently validated. This study provides an integrative representation of the stepwise human Th17 differentiation program and offers new perspectives toward therapeutic targeting of Th17-related autoimmune diseases.

Automated summary

By analyzing the transcriptome of human Th17 cells, researchers identified three time-regulated modules corresponding to early, late, and persistent stages of differentiation, with inflammatory genes predominantly found in the persistent module and regulatory genes induced in late or persistent stages. Key inflammatory genes identified include IL17A, IL17F, IL26, IL6, IFNG, IFNK, LTA, IL1A, PDGFA, HOPX, and SOX2. This study provides insights into the stepwise differentiation program of human Th17 cells and offers potential therapeutic targets for Th17-related autoimmune diseases.