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

Thelper 17 (TH17) cells are found in the periphery and synovium of patients with rheumatoid arthritis (RA); how-ever, IL-17–targeted interventions have limited efficacy in established RA. Inflammation can induce TH17 cell transdifferentiation into IL-17–negative exTH17 cells, but the role of exTH17 cells in arthritis is unknown. We per-formed TH17 cell lineage tracing in the SKG mouse model of RA. In arthritic mice, synovial TH17 cells transdifferen-tiate into CD44+ exTH17 cells, which are more arthritogenic and sustain inflammation that is IL-17 independent. The exTH17 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 TH17 cells and fibroblast-like synoviocytes (FLSs) via S1P promotes TH17-exTH17 cell conversion. CD44 is necessary for exTH17 cell–mediated arthritis. Our study suggests that FLS expansion during RA progression promotes TH17-exTH17 cell conversion. These results could potentially enable RA precision therapy.