T_H17 cells converted into exT_H17 cells sustain rheumatoid-like IL-17-independent inflammatory arthritis

T helper 17 (T_H17) cells are found in the periphery and synovium of patients with rheumatoid arthritis (RA); however, IL-17-targeted interventions have limited efficacy in established RA. Inflammation can induce T_H17 cell transdifferentiation into IL-17-negative exT_H17 cells, but the role of exT_H17 cells in arthritis is unknown. We performed T_H17 cell lineage tracing in the SKG mouse model of RA. In arthritic mice, synovial T_H17 cells transdifferentiate into CD44⁺ exT_H17 cells, which are more arthritogenic and sustain inflammation that is IL-17 independent. The exT_H17 cell gene signature includes up-regulation of CD44 and sphingosine-1-phosphate receptor 4 (S1PR4) and correlates with the profile of human RA synovial CD4⁺ T cells. We demonstrate that cross-talk between T_H17 cells and fibroblast-like synoviocytes (FLSs) via S1P promotes T_H17-exT_H17 cell conversion. CD44 is necessary for exT_H17 cell-mediated arthritis. Our study suggests that FLS expansion during RA progression promotes T_H17-exT_H17 cell conversion. These results could potentially enable RA precision therapy.