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

Excessive activation of interleukin-17-producing helper T (T_H17) cells can cause autoimmune tissue inflammation. However, how T_H17 cells enhance their pathogenicity within target tissues and whether destabilized regulatory T cells contribute to pathogenic T_H17 cell populations remain unclear. Using a T_H17 cell-dependent autoimmune arthritis model, we demonstrated that T_H17 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 T_H17 clusters, ranging from a CD103⁺ Tcf1^hi stem-like state to a CD200⁺ Egr2^hi 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_H17 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.