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<p>Excessive activation of interleukin-17-producing helper T (T<sub>H</sub>17) cells can cause autoimmune tissue inflammation. However, how T<sub>H</sub>17 cells enhance their pathogenicity within target tissues and whether destabilized regulatory T cells contribute to pathogenic T<sub>H</sub>17 cell populations remain unclear. Using a T<sub>H</sub>17 cell-dependent autoimmune arthritis model, we demonstrated that T<sub>H</sub>17 and regulatory T cells did not undergo significant mutual plasticity, based on lineage-tracing and T cell receptor (TCR) repertoire analyses. Single-cell RNA sequencing of joint CD4<sup>+</sup> T cells revealed three phenotypically distinct T<sub>H</sub>17 clusters, ranging from a CD103⁺ Tcf1<sup>hi</sup> stem-like state to a CD200⁺ Egr2<sup>hi</sup> highly pathogenic state. The phenotypic transition to the CD200⁺ pathogenic state was not a default progression driven by inflammatory cues, but rather a highly selective process mediated by tissue-restricted secondary TCR engagement within inflamed joints. Our findings delineate the heterogeneity and pathogenic potential of arthritogenic T<sub>H</sub>17 cells, highlighting secondary autoimmune TCR signaling as a critical regulatory determinant of their developmental trajectories that may serve as a therapeutic target for autoimmune arthritis.</p>

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Tissue-restricted secondary TCR engagement drives the transition from stem-like to CD200+ Egr2hi arthritogenic Th17 cells

  • 期刊论文

  • 发表日期：

    2026年3月23日

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  • Yusuke Takeuchi,
  • Daiya Ohara,
  • Hitomi Watanabe,
  • Yuji Nishimura,
  • Takeshi Iwasaki,
  • Shohei Hori,
  • Hiroshi Kawamoto,
  • Hiroki Kato,
  • Gen Kondoh,
  • Akio Morinobu,
  • Tsuneyo Mimori,
  • Keiji Hirota

摘要

Excessive activation of interleukin-17-producing helper T (TH17) cells can cause autoimmune tissue inflammation. However, how TH17 cells enhance their pathogenicity within target tissues and whether destabilized regulatory T cells contribute to pathogenic TH17 cell populations remain unclear. Using a TH17 cell-dependent autoimmune arthritis model, we demonstrated that TH17 and regulatory T cells did not undergo significant mutual plasticity, based on lineage-tracing and T cell receptor (TCR) repertoire analyses. Single-cell RNA sequencing of joint CD4+ T cells revealed three phenotypically distinct TH17 clusters, ranging from a CD103⁺ Tcf1hi stem-like state to a CD200⁺ Egr2hi highly pathogenic state. The phenotypic transition to the CD200⁺ pathogenic state was not a default progression driven by inflammatory cues, but rather a highly selective process mediated by tissue-restricted secondary TCR engagement within inflamed joints. Our findings delineate the heterogeneity and pathogenic potential of arthritogenic TH17 cells, highlighting secondary autoimmune TCR signaling as a critical regulatory determinant of their developmental trajectories that may serve as a therapeutic target for autoimmune arthritis.