Premium
Polyfunctional, Proinflammatory, Tissue‐Resident Memory Phenotype and Function of Synovial Interleukin‐17A+ CD 8+ T Cells in Psoriatic Arthritis
Author(s) -
Steel Kathryn J. A.,
Srenathan Ushani,
Ridley Michael,
Durham Lucy E.,
Wu ShihYing,
Ryan Sarah E.,
Hughes Catherine D.,
Chan Estee,
Kirkham Bruce W.,
Taams Leonie S.
Publication year - 2020
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.41156
Subject(s) - immunophenotyping , proinflammatory cytokine , immunology , interleukin 17 , t cell , synovial fluid , medicine , t cell receptor , interleukin , flow cytometry , microbiology and biotechnology , biology , inflammation , cytokine , pathology , immune system , alternative medicine , osteoarthritis
Objective Genetic associations imply a role for CD 8+ T cells and the interleukin‐23 ( IL ‐23)/ IL ‐17 axis in psoriatic arthritis (PsA) and other spondyloarthritides (SpA). IL ‐17A+ CD 8+ (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. Methods Peripheral 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 ( TCR β) 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+ CD 8+ T cells were predominantly TCR αβ+ 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). TCR β 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 / IL 23R/ CCR 6 / CD 161 ) 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 CXCR 6 as a marker for synovial Tc17 cells, and increased levels of CXCR 6 ligand CXCL 16 in PsA SF ( P = 0.0005), which may contribute to their retention in the joint. Conclusion Our results identify synovial Tc17 cells as a polyclonal subset of Trm cells characterized by polyfunctional, proinflammatory mediator production and CXCR 6 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.