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

Abstract

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-17^pos) CD4 (P < 0.0001) and CD8 (P < 0.0001), and GM-CSF^pos 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-17^pos Th₁₇ and Th₁₇-derived but not Th₁ cells were expanded by metabolic stress, and metabolic stress may itself represent a unique therapeutic target.