Single-cell profiling reveals CCL5Hi GZMAHi effector memory CD8 T cell association to oligoarticular JIA

OBJECTIVES: Oligoarticular JIA (oligo JIA) is the most common JIA subtype and is often complicated by uveitis, a potentially sight-threatening comorbidity. Despite its prevalence, the immunopathogenic mechanisms underlying oligo JIA and its extra-articular manifestations remain poorly understood. The objective was to characterize the immune landscape of oligo JIA and identify pathogenic cell populations and regulatory mechanisms associated with the disease and uveitis. METHODS: Single-cell RNA and TCR sequencing (scRNA/TCR-Seq) was performed on peripheral blood mononuclear cells (PBMCs) and paired SF from three treatment-naïve, new-onset oligo JIA patients, on PBMC from four oligo JIA patients with uveitis flare and from four age-matched healthy controls (HCs) (discovery cohort; n = 14 samples). Cellular composition, gene expression and T cell clonality were analysed. Key findings were validated by mass cytometry (CyTOF) in an independent cohort of 13 oligo JIA patients, eight uveitis flare patients and six HCs. RESULTS: scRNA-seq of 132 824 immune cells revealed enrichment of activated effector memory CD8+ T cells (CD8+TEM), intermediate monocytes and regulatory T cells in SF. CD8+TEM were depleted in blood, suggesting a recruitment from the circulation into the inflamed joint. SF CD8+TEM displayed upregulation of CCL5, GZMA and GNLY and showed marked clonal expansion. In patients with uveitis, MAIT cells were clonally expanded and transcriptionally reprogrammed with IFN-stimulated and cytotoxic signatures. CyTOF confirmed reduced circulating CCL5Hi GZMAHi CD8+TEM in oligo JIA. CONCLUSIONS: Clonally expanded, cytotoxic CD8+ TEM cells drive joint inflammation in oligo JIA, while activated MAIT and NK cells in uveitis indicate systemic immune activation and potential therapeutic targets.