ROR?t expression in mature Th17 cells safeguard the lineage stability by inhibiting conversion to Th2 cells [ATAC-seq]

ROR?t is the lineage-specific transcription factor for T helper 17 (Th17) cells and an attractive drug target for treating Th17-associated diseases. Though the critical role of ROR?t in early Th17 cell differentiation has been well recognized, whether it maintains mature Th17 cell phenotypes remains largely unexplored. Here, we show that genetic deletion of Rorc in mature Th17 cells inhibited their pathogenic functions. Mechanistically, loss of ROR?t led to a closed chromatin structure at key Th17-specific gene loci, particularly at those so called “super enhancer” regions. Furthermore, RORc deletion in effector Th17 cells resulted in a strongly Th2-biased cell phenotype at both epigenetic and transcriptional levels, in an IL-4-dependent manner. Our results thus reveal a crucial function of ROR?t in effector Th17 cells in maintaining Th17 cell program and constraining Th2 cell conversion, offering new considerations in therapeutic targeting of ROR?t. Overall design: ATAC-seq of WT and 4-OHT induced Rorc KO in vitro cultured Th17 cells.