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 (T_H17) cells and an attractive drug target for treating T_H17-associated diseases. Although the critical role of RORγt in early T_H17 cell differentiation has been well recognized, its function in mature T_H17 cell maintenance remains largely unknown. Here, we show that genetic deletion of Rorc in mature T_H17 cells inhibited their pathogenic functions. Mechanistically, loss of RORγt led to a closed chromatin configuration at key T_H17-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 T_H17 cells to T_H2-like cells in vitro and in vivo. Our results thus reveal dual crucial functions of RORγt in effector T_H17 cells in maintaining T_H17 cell program and constraining T_H2 cell conversion, offering previously unidenified considerations in therapeutic targeting of RORγt.