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.