A cell-intrinsic glucocorticoid biosynthesis and sensing circuit maintains a homeostatic Th17 cell state

T helper 17 (Th17) cells are heterogeneous: homeostatic Th17 (Th17 Hom ) cells maintain tissue homeostasis, and pro-inflammatory Th17 (Th17 Inf ) cells drive autoimmune inflammation. IL-23 drives Th17 Inf , but the signals that maintain Th17 Hom remain unclear. Here, we found that differential glucocorticoid (GC) production downstream of CYP11A1, a critical enzyme for steroidogenesis, distinguished Th17 Hom cells from Th17 Inf cells. Although TCR signaling opened the Cyp11a1 locus, TGF-β1 and IL-6, key cytokines for Th17 Hom cell differentiation, maintained and amplified Cyp11a1 . Th17 Hom cell-derived GC signaled through the glucocorticoid receptor (GR), which was higher in Th17 Hom cells compared with Th17 Inf cells, thereby forming a circuit that maintained the homeostatic state. Integration of multi-omics data from CYP11A1- and GR-deficient Th17 Hom cells revealed a gene network underlying this circuit. TGF-β1, a key node in the network, restored GC sensing to Th17 Inf . We thus identify a GC signaling circuit that maintains Th17 homeostasis with implications for treating Th17-mediated autoimmunity.