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.