Single-cell sequencing reveals a clonal expansion of pro-inflammatory synovial CD8 T cells expressing tissue homing receptors in psoriatic arthritis

Abstract

24 Psoriatic arthritis (PsA) is a debilitating immune-mediated inflammatory arthritis of unknown pathogenesis 25 commonly affecting patients with skin psoriasis. We used three complementary single cell approaches to 26 study leukocytes from PsA joints. Mass cytometry (CyTOF) demonstrated marked (>3 fold) expansion of 27 memory CD8 T cells in the joints compared to matched blood. Further exploration of the memory CD8 28 compartment using both droplet and plate based single cell RNA sequencing of paired alpha and beta chain 29 T cell receptor sequences identified pronounced CD8 T cell clonal expansions within the joints, strongly 30 suggesting antigen driven expansion. These clonotypes exhibited distinct gene expression profiles including 31 cycling, activation, tissue homing and tissue residency markers. Pseudotime analysis of these clonal CD8 32 populations identified trajectories in which tissue residency can represent an intermediate developmental 33 state giving rise to activated, cycling and exhausted CD8 populations. Comparing T-cell clonality across 34 patients further revealed specificity convergence of clones against a putative common antigen. We identify 35 chemokine receptor CXCR3 as upregulated in expanded synovial clones, and elevation of two CXCR3 ligands, 36 CXCL9 and CXCL10, in PsA synovial fluid. 37 38 39 Up to one third of patients suffering from psoriasis develop the debilitating immune-mediated inflammatory 40 joint disease, psoriatic arthritis (PsA) 1 . The pathogenesis of PsA is complex, involving multiple inflammatory 41 pathways 2 . Genome-wide association studies of both psoriasis and PsA support a pathogenic role for CD8 T cells,