RORγt expression in mature Th17 cells safeguard the lineage stability by inhibiting conversion to Th2 cells [RNA-Seq]

RORγt 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 RORγt 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 RORγt 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 RORγt in effector Th17 cells in maintaining Th17 cell program and constraining Th2 cell conversion, offering new considerations in therapeutic targeting of RORγt. RNA-seq of WT and 4-OHT induced Rorc KO in vitro cultured Th17 cells, and CD4+ T cells isolated from colon tissues of WT and Rorc-Cd4cre naïve T cell transfer induced colitis model.