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 (T H 17) cells and an attractive drug target for treating T H 17-associated diseases. Although the critical role of RORγt in early T H 17 cell differentiation has been well recognized, its function in mature T H 17 cell maintenance remains largely unknown. Here, we show that genetic deletion of Rorc in mature T H 17 cells inhibited their pathogenic functions. Mechanistically, loss of RORγt led to a closed chromatin configuration at key T H 17-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 H 17 cells to T H 2-like cells in vitro and in vivo. Our results thus reveal dual crucial functions of RORγt in effector T H 17 cells in maintaining T H 17 cell program and constraining T H 2 cell conversion, offering previously unidenified considerations in therapeutic targeting of RORγt.