Synovial IL-17A+ CD8+ T cells display a polyfunctional, pro-inflammatory and tissue-resident memory phenotype and function in psoriatic arthritis
OBJECTIVE Genetic associations imply a role for CD8+ T cells and the 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 of patients with PsA and IL-17A blockade is clinically efficacious in PsA/SpA. Our aim was 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 synovial fluid (SF) mononuclear cells were isolated from patients with PsA/SpA. Cells were phenotypically, transcriptionally and functionally analysed by flow cytometry (n=6-18), TCRβ sequencing (n=3), RNA-seq (n=3), RT-qPCR (n=4) and Luminex/ELISA (n=4-16).
RESULTS IL-17A+ CD8+ T cells were predominantly TCRαβ+ and their frequencies were increased in the SF vs. PB of patients with established PsA (p<0.0001) or other SpA (p=0.0009). TCRβ sequencing showed these cells are polyclonal in PsA (median clonality = 0.08), whilst RNA-seq and deep-immunophenotyping revealed that PsA synovial Tc17 cells have hallmarks of Th17 (RORC/IL23R/CCR6/CD161) and Tc1 cells (granzyme A/B). Synovial Tc17 cells showed a strong tissue-resident memory T cell signature and secreted a range of pro-inflammatory cytokines. We identified CXCR6 as a marker for synovial Tc17 cells, and increased levels of CXCR6 ligand CXCL16 levels 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 tissue-resident memory T cells characterised by polyfunctional, pro-inflammatory 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 SpA.