RORγt expression in mature T_H17 cells safeguards their lineage specification by inhibiting conversion to T_H2 cells

RORγt is the lineage-specific transcription factor for T helper 17 (TH17) cells and an attractive drug target for treating TH17-associated diseases. Although the critical role of RORγt in early TH17 cell differentiation has been well recognized, its function in mature TH17 cell maintenance remains largely unknown. 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 configuration at key TH17-specific gene loci, particularly at the "super-enhancer" regions. Unexpectedly, RORγt directly bound and inhibited Il4 transcription, whereas pharmaceutically or genetically targeting RORγt caused spontaneous conversion of TH17 cells to TH2-like cells in vitro and in vivo. Our results thus reveal dual crucial functions of RORγt in effector TH17 cells in maintaining TH17 cell program and constraining TH2 cell conversion, offering previously unidenified considerations in therapeutic targeting of RORγt.