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

Abstract

Psoriatic arthritis (PsA) is a debilitating immune-mediated inflammatory arthritis of unknown pathogenesis commonly affecting patients with skin psoriasis. We used three complementary single cell approaches to study leukocytes from PsA joints. Mass cytometry (CyTOF) demonstrated marked (>3 fold) expansion of memory CD8 T cells in the joints compared to matched blood. Further exploration of the memory CD8 compartment using both droplet and plate based single cell RNA sequencing of paired alpha and beta chain T cell receptor sequences identified pronounced CD8 T cell clonal expansions within the joints, strongly suggesting antigen driven expansion. These clonotypes exhibited distinct gene expression profiles including cycling, activation, tissue homing and tissue residency markers. Pseudotime analysis of these clonal CD8 populations identified trajectories in which tissue residency can represent an intermediate developmental state giving rise to activated, cycling and exhausted CD8 populations. Comparing T-cell clonality across patients further revealed specificity convergence of clones against a putative common antigen. We identify chemokine receptor CXCR3 as upregulated in expanded synovial clones, and elevation of two CXCR3 ligands, CXCL9 and CXCL10, in PsA synovial fluid.