Abstract
Psoriatic arthritis (PsA) is a debilitating immune-mediated inflammatory arthritis of unknown pathogenesis commonly affecting patients with skin psoriasis. Here we use complementary single-cell approaches to study leukocytes from PsA joints. Mass cytometry demonstrates a 3-fold expansion of memory CD8 T cells in the joints of PsA patients compared to peripheral blood. Meanwhile, droplet-based and plate-based single-cell RNA sequencing of paired T cell receptor alpha and beta chain sequences show pronounced CD8 T cell clonal expansions within the joints. Transcriptome analyses find these expanded synovial CD8 T cells to express cycling, activation, tissue-homing and tissue residency markers. T cell receptor sequence comparison between patients identifies clonal convergence. Finally, chemokine receptor CXCR3 is upregulated in the expanded synovial CD8 T cells, while two CXCR3 ligands, CXCL9 and CXCL10, are elevated in PsA synovial fluid. Our data thus provide a quantitative molecular insight into the cellular immune landscape of psoriatic arthritis.
Highlights
Psoriatic arthritis (PsA) is a debilitating immune-mediated inflammatory arthritis of unknown pathogenesis commonly affecting patients with skin psoriasis
We identify clonal expansions of CD8 T cells in PsA synovial fluid, show that single alpha–beta T-cell sister clones exist in multiple cell states and highlight pathways that mediate their trafficking into the joint
Isolated peripheral blood and synovial fluid were obtained from patients with large-joint oligo PsA presenting for arthrocentesis, and immediately (0.5–4 h) processed for mass cytometry (CyTOF) and single-cell RNA sequencing (Fig. 1a, b)
Summary
Psoriatic arthritis (PsA) is a debilitating immune-mediated inflammatory arthritis of unknown pathogenesis commonly affecting patients with skin psoriasis. Droplet-based and plate-based single-cell RNA sequencing of paired T cell receptor alpha and beta chain sequences show pronounced CD8 T cell clonal expansions within the joints. Costello and colleagues identified an average of 32 private T-cell receptor (TCR) beta-chain clonal expansions unique to individual patients and primarily confined to synovial fluid While they found evidence supporting antigen-driven selection, with differing nucleic acid sequences encoding common amino acid sequences, they did not see evidence of shared or public repertoires between different patients, as previously described for HLA-B27-associated spondyloarthritis[5]. We identify clonal expansions of CD8 T cells in PsA synovial fluid, show that single alpha–beta T-cell sister clones exist in multiple cell states and highlight pathways that mediate their trafficking into the joint These findings have implications for our understanding of the pathogenesis of PsA and other HLAassociated immune-mediated inflammatory diseases, as well as suggesting potential therapeutic approaches
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