Schwarz Tobias, Almanzar Giovanni, Wulfheide Marie, Woidich Robert, Holzer Marie-Therese, Christoforou Timotheos, Karle Leonie, Radtke David, Brauneiser Franziska, Haaf Thomas, Potabattula Ramya, Ortega Gabriela, Lesch Klaus-Peter, Schäfer Arne, Benoit Sandrine, Schmieder Astrid, Goebeler Matthias, Schmalzing Marc, Feuchtenberger Martin, Prelog Martina
Department of Pediatrics, Pediatric Rheumatology/Special Immunology, University Hospital Wuerzburg, 97080 Wuerzburg, Germany.
Department of Human Genetics, University of Wuerzburg, 97074 Wuerzburg, Germany.
Int J Mol Sci. 2025 Jul 29;26(15):7339. doi: 10.3390/ijms26157339.
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, mRNA expression, CpG methylation of the 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 promotor and Treg-specific demethylated region (TSDR) in Treg cells which, however, resulted neither in elevated 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 mRNA expression due to hypermethylation of the promotor and TSDR. This potential causal relationship between Th17 inflammation and impaired Treg cell function requires attention regarding the development of immunomodulatory therapies.
考虑到FoxP3调节性T（Treg）细胞和产生白细胞介素（IL）-17的Th17细胞具有高度可塑性，我们推测Th17炎症微环境可能会损害慢性炎症性关节炎中Treg细胞的功能特性。因此，我们对银屑病关节炎（PsoA）、类风湿关节炎或脊柱关节炎患者进行了横断面探索性分析，以研究Th17细胞和Treg细胞的特征。我们测定了T细胞亚群计数、基因的mRNA表达、CpG甲基化以及分离出的Treg细胞的抑制能力。对PsoA患者外周血淋巴细胞的体外分析显示存在Th17介导的炎症。这伴随着Treg细胞中启动子和Treg特异性去甲基化区域（TSDR）的去甲基化，然而，这既未导致mRNA表达升高，也未使Treg细胞的抑制能力增加。为了阐明这一难题，我们用诱导Th17的细胞因子（IL-1β、IL-6、IL-23、TGFβ）、重组IL-17或抗IL-17A抗体司库奇尤单抗对分离出的Treg细胞进行了体外刺激，结果表明，向Th17极化的细胞培养条件而非IL-17本身会损害Treg细胞的抑制功能，同时由于启动子和TSDR的高甲基化导致mRNA表达减少。Th17炎症与Treg细胞功能受损之间的这种潜在因果关系在免疫调节疗法的开发中需要引起关注。
