Artikel
Impaired FoxP3+ Treg function and epigenetic modulations at the FoxP3 enhancer, promotor and TSDR regions by Th17-inducing cytokines in patients with psoriatic arthritis
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Veröffentlicht: | 14. September 2021 |
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Gliederung
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Introduction: Th17 helper T cells have been proposed to play an essential role in the pathogenesis of psoriatic arthritis (PsA), whereas FoxP3+ regulatory T cells (Treg) are able to modulate T-cell-mediated inflammation. Anti-IL-17A therapies have been successfully used in PsA patients and, thus, the influence of the Th17-milieu on Treg function came into focus in order to understand whether targeting IL-17 may enhance intrinsic regulatory functions of Treg cells.
The present study aimed to analyze the effect of Th17-stimulating cytokines on the phenotype and function of FoxP3+ Treg derived from therapy-naive PsA patients by simulating Th17-inducing cell culture conditions in vitro by a cytokine cocktail consisting of IL-1, IL-6, IL-23 and TGF-beta. Particular emphasis was put on the plasticity of Treg considering also methylation at the FoxP3 regulatory gene regions.
Methods: Therefore, peripheral lymphocytes of 10 PsA patients and 12 healthy controls (HC) were isolated to investigate the proportions of functionally active Treg by flow cytometry and CFSE-based suppression assays with magnetically separated Treg on autologous effectors. Expression of FoxP3 was analyzed by quantitative PCR. Methylation was determined at the enhancer, promotor and TSDR regions of FoxP3 by bisulfite conversion and pyrosequencing.
Results: Significantly higher percentages of Th17 and chemokine receptor-expressing helper T cells were found in PsA and further elevations were seen upon exposing PsA-derived lymphocytes to Th17-stimulating cytokines in vitro. A higher proportion of Th17-like Treg cells displaying features of both Th17 and Treg cells was demonstrated in PsA. Th17-stimulating cytokines reduced the ability of Treg to inhibit proliferation of autologous effectors in vitro. A Th17-stimulating milieu increased the methylation at FoxP3 gene regions in isolated CD25+ Treg cells and caused lower transcription of FoxP3 in both PsA and HC.
Conclusion: The findings showed similar effects of Th17-inducing cytokines on peripheral lymphocytes and isolated Treg cells of PsA and HC patients and underline the unfavorable influence of Th17-inducing cytokines on the potential self-ability of the immune system to modulate proliferation of effectors by autologous Treg cells.
Disclosures: Parts of the study were funded by Novartis.