RORγt expression in mature T H 17 cells safeguards their lineage specification by inhibiting conversion to T H 2 cells.

RORγt is the lineage-specific transcription factor for T helper 17 (T17) cells and an attractive drug target for treating T17-associated diseases. Although the critical role of RORγt in early T17 cell differentiation has been well recognized, its function in mature T17 cell maintenance remains largely unknown. Here, we show that genetic deletion of in mature T17 cells inhibited their pathogenic functions. Mechanistically, loss of RORγt led to a closed chromatin configuration at key T17-specific gene loci, particularly at the "super-enhancer" regions. Unexpectedly, RORγt directly bound and inhibited transcription, whereas pharmaceutically or genetically targeting RORγt caused spontaneous conversion of T17 cells to T2-like cells in vitro and in vivo. Our results thus reveal dual crucial functions of RORγt in effector T17 cells in maintaining T17 cell program and constraining T2 cell conversion, offering previously unidenified considerations in therapeutic targeting of RORγt.