Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
Institute of Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
Front Immunol. 2023 Apr 6;14:1094694. doi: 10.3389/fimmu.2023.1094694. eCollection 2023.
Treg cells have been shown to be an important part of immune-homeostasis and IL-2 which is produced upon T cell receptor (TCR)-dependent activation of T lymphocytes has been demonstrated to critically participate in Treg development.
To evaluate small molecule inhibitors (SMI) for the identification of novel IL-2/Treg enhancing compounds.
We used TCR-dependent and allergen-specific cytokine secretion of human and mouse T cells, next generation messenger ribonucleic acid sequencing (RNA-Seq) and two different models of allergic airway inflammation to examine lead SMI-compounds.
We show here that the reported 3-phosphoinositide dependent kinase-1 (PDK1) SMI BX-795 increased IL-2 in culture supernatants of Jurkat E6-1 T cells, human peripheral blood mononuclear cells (hPBMC) and allergen-specific mouse T cells upon TCR-dependent and allergen-specific stimulation while concomitantly inhibiting Th2 cytokine secretion. RNA-Seq revealed that the presence of BX-795 during allergen-specific activation of T cells induces a Treg cell type highly similar to iTreg but lacking Foxp3 expression. When applied in mugwort pollen and house dust mite extract-based models of airway inflammation, BX-795 significantly inhibited Th2 inflammation including expression of Th2 signature transcription factors and cytokines and influx into the lungs of type 2-associated inflammatory cells such as eosinophils.
BX-795 potently uncouples IL-2 production from Th2 inflammation and induces Th-IL-2 cells, which highly resemble induced (i)Tregs. Thus, BX-795 may be a useful new compound for the treatment of allergic diseases.
调节性 T 细胞（Treg 细胞）已被证明是免疫稳态的重要组成部分，而白细胞介素 2（IL-2）在 T 淋巴细胞的 T 细胞受体（TCR）依赖性激活后产生，已被证明在 Treg 细胞的发育中起着至关重要的作用。
评估小分子抑制剂（SMI）以鉴定新型的 IL-2/Treg 增强化合物。
我们使用 TCR 依赖性和过敏原特异性细胞因子分泌的人源和鼠源 T 细胞、下一代信使核糖核酸测序（RNA-Seq）以及两种不同的变应性气道炎症模型来检测先导 SMI 化合物。
我们在此表明，报道的 3-磷酸肌醇依赖性激酶-1（PDK1）SMI BX-795 可增加 Jurkat E6-1 T 细胞、人外周血单核细胞（hPBMC）和过敏原特异性鼠源 T 细胞在 TCR 依赖性和过敏原特异性刺激时培养上清液中的 IL-2，同时抑制 Th2 细胞因子的分泌。RNA-Seq 显示，在 T 细胞的过敏原特异性激活过程中存在 BX-795 会诱导一种与 iTreg 高度相似但缺乏 Foxp3 表达的 Treg 细胞类型。当应用于艾蒿花粉和屋尘螨提取物为基础的气道炎症模型时，BX-795 可显著抑制 Th2 炎症，包括 Th2 特征性转录因子和细胞因子的表达以及 2 型相关炎症细胞如嗜酸性粒细胞向肺部的浸润。
BX-795 可有效分离 IL-2 产生与 Th2 炎症，并诱导 Th-IL-2 细胞，其高度类似于诱导性（i）Treg 细胞。因此，BX-795 可能是治疗变应性疾病的一种有用的新型化合物。
