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

Carmel B Stober; Louise Ellis; Jane C Goodall; Marc Veldhoen; J S Hill Gaston

doi:10.1002/art.43095

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

Arthritis Rheumatol. 2024 Dec 22. doi: 10.1002/art.43095. Online ahead of print.

Authors

Carmel B Stober^{1

2}, Louise Ellis¹, Jane C Goodall¹, Marc Veldhoen^{3

4

5}, J S Hill Gaston¹

Affiliations

¹ Department of Medicine, University of Cambridge, Cambridge University Hospitals NHS FT, Cambridge, U.K.
² Department of Rheumatology, Addenbrooke's Hospital, Cambridge University Hospitals NHS FT, Cambridge, U.K.
³ Laboratory for Lymphocyte Signalling and Development, The Babraham Institute, Cambridge, CB22 3AT, UK.
⁴ GIMM - Gulbenkian Institute for Molecular Medicine, Avenida Prof. Egas Moniz, 1649-035, Lisbon, Portugal.
⁵ Faculdade de Medicina da Universidade de Lisboa, Avenida Prof. Egas Moniz, 1649-028, Lisbon, Portugal.

PMID: 39711043
DOI: 10.1002/art.43095

Abstract

Objective: Genetic 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.

Methods: PsA 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.

Results: Polyfunctional IL-17^pos CD4 (p<0.0001) & CD8 (p<0.0001), and GM-CSF^pos 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.

Conclusions: We 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-17^pos Th₁₇, and Th₁₇-derived but not Th₁ cells, were expanded by metabolic stress, where metabolic stress may itself represent a unique therapeutic target.