Metabolic Stress expands Polyfunctional, Proinflammatory Th17 cells in Psoriatic Arthritis, where there is IL‐23‐independent IL‐17 production

Abstract

ObjectiveGenetic associations and blockade of the interleukin‐23/IL‐17 axis with monoclonal antibodies support a role for this pathway in psoriatic arthritis (PsA). This study examines the requirement of IL‐23 for IL‐17 production, and the role of the metabolic microenvironment in the expansion of Th17‐derived cells in PsA.MethodsPsA patient synovial fluid or peripheral blood Th17 cell frequencies were evaluated by flow cytometry using CCR6, CD161 and T‐bet as phenotypic markers, and the cytokines IFN‐γ, GM‐CSF and IL‐17 assessed by flow cytometry and ELISA. The impact of IL‐23 and metabolic stress on T cell differentiation was investigated.ResultsPolyfunctional IL‐17pos CD4 (p<0.0001) & CD8 (p<0.0001), and GM‐CSFpos Th17‐derived (p<0.0001) cells were increased in inflamed joints of patients with PsA, with a proportional decrease in patient peripheral blood. We demonstrate IL‐23‐independent IL‐17 release by PsA patient CD4 T cells, where the absence of IL‐23 during Th17 differentiation reduced IL‐17 by 31±5.8%. Exogenous IL‐23 increased IL‐17, negatively regulated GM‐CSF and co‐operated with TGF‐β to augment IL‐17. Polyfunctional Th17 and Th17‐derived cells, but not Th1 cells, were expanded by metabolic stress in patients with PsA.ConclusionsWe confirmed the abundance of polyfunctional Type17 CD4 and CD8 cells in PsA inflamed joints. We demonstrate IL‐23‐independent expansion of Th17 cells, where IL‐23 negatively regulates GM‐CSF. This may account for therapeutic differences in IL‐17 and IL‐23 inhibition in PsA and the Spondyloarthritides. Polyfunctional IL‐17pos Th17, and Th17‐derived but not Th1 cells, were expanded by metabolic stress, where metabolic stress may itself represent a unique therapeutic target.