Metabolic Stress Expands Polyfunctional, Proinflammatory Th17 Cells in Patients With Psoriatic Arthritis for Whom There is Interleukin-23-Independent Interleukin-17 Production.

OBJECTIVE: Genetic associations and blockade of the interleukin (IL)-23/IL-17 axis with monoclonal antibodies support a role for this pathway in patients with 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 patients with PsA. METHODS: Th17 cell frequencies in synovial fluid or peripheral blood from patients with PsA were evaluated by flow cytometry using chemokine receptor 6, CD161, and T-bet as phenotypic markers, and the cytokines interferon γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-17 were assessed by flow cytometry and enzyme-linked immunosorbent assay. The impact of IL-23 and metabolic stress on T cell differentiation was investigated. RESULTS: Polyfunctional positive IL-17 (IL-17pos) CD4 (P < 0.0001) and CD8 (P < 0.0001), and GM-CSFpos Th17-derived cells (P < 0.0001) were increased in the inflamed joints of patients with PsA, with a proportional decrease in the peripheral blood of patients. We demonstrate IL-23-independent IL-17 release by CD4 T cells in patients with PsA, in which the absence of IL-23 during Th17 differentiation reduced IL-17 by mean ± SEM 31% ± 5.8%. Exogenous IL-23 increased IL-17, negatively regulated GM-CSF, and cooperated with transforming growth factor β to augment IL-17. Polyfunctional Th17 and Th17-derived cells, but not Th1 cells, were expanded by metabolic stress in patients with PsA. CONCLUSION: We confirmed the abundance of polyfunctional type 17 CD4 and CD8 cells in the inflamed joints of patients with PsA. We demonstrate IL-23-independent expansion of Th17 cells, for which IL-23 negatively regulates GM-CSF. This may account for therapeutic differences in IL-17 and IL-23 inhibition in patients with PsA or other spondyloarthritides. Polyfunctional IL-17pos Th17 and Th17-derived but not Th1 cells were expanded by metabolic stress, and metabolic stress may itself represent a unique therapeutic target.