T H 17 cells converted into exT H 17 cells sustain rheumatoid-like IL-17–independent inflammatory arthritis

T helper 17 (T H 17) 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 H 17 cell transdifferentiation into IL-17–negative exT H 17 cells, but the role of exT H 17 cells in arthritis is unknown. We performed T H 17 cell lineage tracing in the SKG mouse model of RA. In arthritic mice, synovial T H 17 cells transdifferentiate into CD44 + exT H 17 cells, which are more arthritogenic and sustain inflammation that is IL-17 independent. The exT H 17 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 H 17 cells and fibroblast-like synoviocytes (FLSs) via S1P promotes T H 17-exT H 17 cell conversion. CD44 is necessary for exT H 17 cell–mediated arthritis. Our study suggests that FLS expansion during RA progression promotes T H 17-exT H 17 cell conversion. These results could potentially enable RA precision therapy.