This study investigates the pathogenic role of Foxp3+ T cells converting into TH17 cells in autoimmune arthritis. The authors found that under arthritic conditions, CD25loFoxp3+CD4+ T cells lose Foxp3 expression and differentiate into TH17 cells, which are more potent osteoclastogenic cells than naive CD4+ T cell-derived TH17 cells. These exFoxp3 TH17 cells accumulate in inflamed joints and are characterized by the expression of specific markers such as Sox4, CCR6, CCL20, IL-23R, and RANKL. The conversion of Foxp3+ T cells to TH17 cells is mediated by synovial fibroblast-derived IL-6. Adoptive transfer of autoreactive, antigen-experienced CD25loFoxp3+CD4+ T cells into mice accelerated the onset and severity of arthritis. The presence of exFoxp3 TH17 cells was also observed in the synovium of subjects with active rheumatoid arthritis. These findings highlight the pathological importance of Foxp3 instability in generating pathogenic TH17 cells in autoimmune diseases.This study investigates the pathogenic role of Foxp3+ T cells converting into TH17 cells in autoimmune arthritis. The authors found that under arthritic conditions, CD25loFoxp3+CD4+ T cells lose Foxp3 expression and differentiate into TH17 cells, which are more potent osteoclastogenic cells than naive CD4+ T cell-derived TH17 cells. These exFoxp3 TH17 cells accumulate in inflamed joints and are characterized by the expression of specific markers such as Sox4, CCR6, CCL20, IL-23R, and RANKL. The conversion of Foxp3+ T cells to TH17 cells is mediated by synovial fibroblast-derived IL-6. Adoptive transfer of autoreactive, antigen-experienced CD25loFoxp3+CD4+ T cells into mice accelerated the onset and severity of arthritis. The presence of exFoxp3 TH17 cells was also observed in the synovium of subjects with active rheumatoid arthritis. These findings highlight the pathological importance of Foxp3 instability in generating pathogenic TH17 cells in autoimmune diseases.