Single cell characterisation of tissue homing CD4+ and CD8+ T cell clones in immune-mediated refractory arthritis

Abstract

Abstract Background: Immune-mediated arthritis (IMA) is a group of autoimmune diseases where chronic inflammation primarily targets different joints in the body. Rheumatoid Arthritis (RA) is the most common subtype. In childhood, RA mostly manifests as juvenile idiopathic arthritis (JIA). In this study, we aimed to characterize the tissue homing inflammatory pathogenic T cells in patients with IMA. Methods: We collected paired synovial tissue (ST) and peripheral blood (PB) samples from three patients with IMA and analyzed CD45+, CD4+ and CD8+ sorted cells with paired single-cell RNA and TCRα/β sequencing and validated the findings with published datasets. Results: Despite being disparate diseases, CD4+ T cells in IMA represented uniform phenotype across patients with no major patient specific clusters. The ST cells were more cytotoxic (GZMB), highly activated (LAG3, PDCD1) and proliferative (NME1, FABP5, G0S2and MKI67). A modest clonal expansion within the Treg cluster was found in the ST compartment as compared to PB (p<0.05). Conversely, the CD8+ T cell clusters showed strong patient specific characteristics. All T cell clones enriched to the ST upregulated genes belonging to TNF receptor superfamilies, inflammation markers (LMNA, RGCC, CREM), and transcription factor NR4A2. Pathway enrichment analysis showed enrichment of the TNFA signalling via NFKB and apoptosis pathways. Conclusions: Our data suggests that in patients with IMA, the synovial tissue is dominated with cytotoxic, highly activated CD4+ T cells with proliferation-associated gene expression signature. Shared CD4+ and CD8+ T cell clones can be found between PB and ST, but they have a more proliferative and activated phenotype when trafficking from PB to ST. Supported by grants from University of Helsinki, Finland