Single-cell profiling reveals CCL5Hi GZMAHi effector memory CD8 T cell association to oligoarticular juvenile idiopathic arthritis.

Abstract

Oligoarticular juvenile idiopathic arthritis (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. Single-cell RNA and TCR sequencing (scRNA/TCR-Seq) was performed on peripheral blood mononuclear cells (PBMC) and paired synovial fluid (SF) from 3 treatment-naïve, new-onset oligo JIA patients, on PBMC from 4 oligo JIA patients with uveitis flare, and from 4 age-matched healthy controls (HC) (discovery cohort; n = 14 samples). Cellular composition, gene expression, and T cell clonality were analyzed. Key findings were validated by mass cytometry (CyTOF) in an independent cohort of 13 oligo JIA patients, 8 uveitis flare patients, and 6 healthy controls. 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 interferon-stimulated and cytotoxic signatures. CyTOF confirmed reduced circulating CCL5Hi GZMAHi CD8+TEM in oligo JIA. 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.