RORγt expression in mature TH17 cells safeguards their lineage specification by inhibiting conversion to TH2 cells

ROR gamma t 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 ROR gamma t 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 ROR gamma t led to a closed chromatin configuration at key T(H)17-specific gene loci, particularly at the "super-enhancer" regions. Unexpectedly, ROR gamma t directly bound and inhibited Il4 transcription, whereas pharmaceutically or genetically targeting ROR gamma t 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 ROR gamma t 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 ROR gamma t.