Influence of a Th17-Inducing Cytokine Milieu on Phenotypical and Functional Properties of Regulatory T Cells in...

Considering the high plasticity of FoxP3⁺ regulatory T (Treg) cells and Interleukin (IL)-17-producing Th17 cells, we hypothesized that a Th17 inflammatory milieu may impair the functional properties of Treg cells in chronic inflammatory arthritides. Therefore, a cross-sectional explorative analysis was set up in patients with psoriatic arthritis (PsoA), rheumatoid arthritis, or spondyloarthritis to investigate the features of Th17 and Treg cells. T cell subpopulation counts, FOXP3 mRNA expression, CpG methylation of the FOXP3 gene, and the suppressive capacity of isolated Treg cells were determined. Ex vivo analysis of PsoA-derived peripheral blood lymphocytes showed a Th17-mediated inflammation. It was accompanied by demethylation of the FOXP3 promotor and Treg-specific demethylated region (TSDR) in Treg cells which, however, resulted neither in elevated FOXP3 mRNA expression nor in increased suppressive Treg cell capacity. To clarify this conundrum, in vitro stimulation of isolated Treg cells with Th17-inducing cytokines (IL-1β, IL-6, IL-23, TGFβ), recombinant IL-17, or the anti-IL-17A antibody secukinumab was performed, demonstrating that cell culture conditions polarizing towards Th17, but not IL-17 itself, impair the suppressive function of Treg cells, accompanied by diminished FOXP3 mRNA expression due to hypermethylation of the FOXP3 promotor and TSDR. This potential causal relationship between Th17 inflammation and impaired Treg cell function requires attention regarding the development of immunomodulatory therapies.