Abstract
ObjectiveGenetic associations imply a role for CD8+ T cells and the interleukin‐23 (IL‐23)/IL‐17 axis in psoriatic arthritis (PsA) and other spondyloarthritides (SpA). IL‐17A+CD8+ (Tc17) T cells are enriched in the synovial fluid (SF) of patients with PsA, and IL‐17A blockade is clinically efficacious in PsA/SpA. This study was undertaken to determine the immunophenotype, molecular profile, and function of synovial Tc17 cells in order to elucidate their role in PsA/SpA pathogenesis.MethodsPeripheral blood (PB) and SF mononuclear cells were isolated from patients with PsA or other types of SpA. Cells were phenotypically, transcriptionally, and functionally analyzed by flow cytometry (n = 6–18), T cell receptor β (TCRβ) sequencing (n = 3), RNA‐Seq (n = 3), quantitative reverse transcriptase–polymerase chain reaction (n = 4), and Luminex or enzyme‐linked immunosorbent assay (n = 4–16).Results IL‐17A+CD8+ T cells were predominantly TCRαβ+ and their frequencies were increased in the SF versus the PB of patients with established PsA (P < 0.0001) or other SpA (P = 0.0009). TCRβ sequencing showed that these cells were polyclonal in PsA (median clonality 0.08), while RNA‐Seq and deep immunophenotyping revealed that PsA synovial Tc17 cells had hallmarks of Th17 cells (RORC/IL23R/CCR6/CD161) and Tc1 cells (granzyme A/B). Synovial Tc17 cells showed a strong tissue‐resident memory T (Trm) cell signature and secreted a range of proinflammatory cytokines. We identified CXCR6 as a marker for synovial Tc17 cells, and increased levels of CXCR6 ligand CXCL16 in PsA SF (P = 0.0005), which may contribute to their retention in the joint.ConclusionOur results identify synovial Tc17 cells as a polyclonal subset of Trm cells characterized by polyfunctional, proinflammatory mediator production and CXCR6 expression. The molecular signature and functional profiling of these cells may help explain how Tc17 cells can contribute to synovial inflammation and disease persistence in PsA and possibly other types of SpA.
Highlights
Psoriatic arthritis (PsA) is part of an umbrella group of inflammatory diseases, termed spondyloarthritides (SpA), that share common patterns of joint inflammation; skin, gut, and eye manifestations; genetic components; and the absence of diagnostic autoantibodies
Our results identify synovial Tc17 cells as a polyclonal subset of Trm cells characterized by polyfunctional, proinflammatory mediator production and CXCR6 expression
The molecular signature and functional profiling of these cells may help explain how Tc17 cells can contribute to synovial inflammation and disease persistence in PsA and possibly other types of SpA
Summary
Psoriatic arthritis (PsA) is part of an umbrella group of inflammatory diseases, termed spondyloarthritides (SpA), that share common patterns of joint inflammation (peripheral and axial); skin, gut, and eye manifestations; genetic components; and the absence of diagnostic autoantibodies (seronegativity). Supported in part by King’s Health Partners R&D Challenge Fund (R140808), Research Councils UK Medical Research Council (grant MR/ P018904/1), Novartis Pharma AG, Versus Arthritis (grant 21139), and the NIHR Biomedical Research Centre at Guy’s and St. Thomas’ NHS Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. Drs Srenathan and Ridley contributed to this work. Drs Kirkham and Taams contributed to this work
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