Tissue-restricted secondary TCR engagement drives the transition from stem-like to CD200 Egr2 arthritogenic Th17 cells.

Excessive activation of interleukin-17-producing helper T (T17) cells can cause autoimmune tissue inflammation. However, how T17 cells enhance their pathogenicity within target tissues and whether destabilized regulatory T cells contribute to pathogenic T17 cell populations remain unclear. Using a T17 cell-dependent autoimmune arthritis model, we demonstrated that T17 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 T17 clusters, ranging from a CD103⁺ Tcf1 stem-like state to a CD200⁺ Egr2 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 T17 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.

© 2026. The Author(s), under exclusive licence to Springer Nature America, Inc.

PMID: 41872507