Pathogenic conversion of Foxp3 + T cells into TH17 cells in autoimmune arthritis

Noriko Komatsu, Kazuo Okamoto, Shinichiro Sawa, Tomoki Nakashima, Masatsugu Oh-Hora, Tatsuhiko Kodama, Sakae Tanaka, Jeffrey A. Bluestone, Hiroshi Takayanagi

    Research output: Contribution to journalArticlepeer-review

    859 Citations (Scopus)


    Autoimmune diseases often result from an imbalance between regulatory T (T reg) cells and interleukin-17 (IL-17)-producing T helper (T H 17) cells; the origin of the latter cells remains largely unknown. Foxp3 is indispensable for the suppressive function of T reg cells, but the stability of Foxp3 has been under debate. Here we show that T H 17 cells originating from Foxp3 + T cells have a key role in the pathogenesis of autoimmune arthritis. Under arthritic conditions, CD25 lo Foxp3 + CD4 + T cells lose Foxp3 expression (herein called exFoxp3 cells) and undergo transdifferentiation into T H 17 cells. Fate mapping analysis showed that IL-17-expressing exFoxp3 T (exFoxp3 T H 17) cells accumulated in inflamed joints. The conversion of Foxp3 + CD4 + T cells to T H 17 cells was mediated by synovial fibroblast-derived IL-6. These exFoxp3 T H 17 cells were more potent osteoclastogenic T cells than were naive CD4 + T cell-derived T H 17 cells. Notably, exFoxp3 T H 17 cells were characterized by the expression of Sox4, chemokine (C-C motif) receptor 6 (CCR6), chemokine (C-C motif) ligand 20 (CCL20), IL-23 receptor (IL-23R) and receptor activator of NF-κB ligand (RANKL, also called TNFSF11). Adoptive transfer of autoreactive, antigen-experienced CD25 lo Foxp3 + CD4 + T cells into mice followed by secondary immunization with collagen accelerated the onset and increased the severity of arthritis and was associated with the loss of Foxp3 expression in the majority of transferred T cells. We observed IL-17 + Foxp3 + T cells in the synovium of subjects with active rheumatoid arthritis (RA), which suggests that plastic Foxp3 + T cells contribute to the pathogenesis of RA. These findings establish the pathological importance of Foxp3 instability in the generation of pathogenic T H 17 cells in autoimmunity.

    Original languageEnglish
    Pages (from-to)62-68
    Number of pages7
    JournalNature medicine
    Issue number1
    Publication statusPublished - 2014

    All Science Journal Classification (ASJC) codes

    • General Biochemistry,Genetics and Molecular Biology


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