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

<h4>Objectives</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.