A promising way to restrain hazardous immune responses, such as autoimmune disease and allergy, is to convert disease-mediating T cells into immunosuppressive regulatory T (Treg) cells. Here, we show that chemical inhibition of the cyclin-dependent kinase 8 (CDK8) and CDK19, or knockdown/knockout of the CDK8 or CDK19 gene, is able to induce Foxp3, a key transcription factor controlling Treg cell function, in antigen-stimulated effector/memory as well as naïve CD4+ and CD8+ T cells. The induction was associated with STAT5 activation, independent of TGF-β action, and not affected by inflammatory cytokines. Furthermore, in vivo administration of a newly developed CDK8/19 inhibitor along with antigen immunization generated functionally stable antigen-specific Foxp3+ Treg cells, which effectively suppressed skin contact hypersensitivity and autoimmune disease in animal models. The results indicate that CDK8/19 is physiologically repressing Foxp3 expression in activated conventional T cells and that its pharmacological inhibition enables conversion of antigen-specific effector/memory T cells into Foxp3+ Treg cells for the treatment of various immunological diseases.

中文翻译：

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通过抑制CDK8 / 19，将抗原特异性效应子/记忆T细胞转化为表达Foxp3的Treg细胞。

抑制有害免疫反应（例如自身免疫性疾病和变态反应）的一种有前途的方法是将介导疾病的T细胞转化为免疫抑制性调节性T（Treg）细胞。在这里，我们显示出对细胞周期蛋白依赖性激酶8（CDK8）和CDK19的化学抑制，或CDK8或CDK19基因的敲除/敲除，能够在抗原刺激下诱导Foxp3，这是控制Treg细胞功能的关键转录因子。效应子/记忆以及未成熟的CD4 +和CD8 + T细胞。诱导与STAT5激活相关，独立于TGF-β作用，且不受炎性细胞因子影响。此外，在体内施用新开发的CDK8 / 19抑制剂并进行抗原免疫可产生功能稳定的抗原特异性Foxp3 + Treg细胞，有效抑制动物模型中的皮肤接触超敏反应和自身免疫性疾病。结果表明，CDK8 / 19在生理上抑制活化的常规T细胞中的Foxp3表达，并且其药理抑制作用使得抗原特异性效应子/记忆T细胞能够转化为Foxp3 + Treg细胞，以治疗各种免疫疾病。