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Conversion of antigen-specific effector/memory T cells into Foxp3-expressing Treg cells by inhibition of CDK8/19.
Science Immunology ( IF 17.6 ) Pub Date : 2019-10-25 , DOI: 10.1126/sciimmunol.aaw2707
Masahiko Akamatsu 1, 2 , Norihisa Mikami 3, 4 , Naganari Ohkura 3, 5 , Ryoji Kawakami 3 , Yohko Kitagawa 3 , Atsushi Sugimoto 3 , Keiji Hirota 4 , Naoto Nakamura 2 , Satoru Ujihara 2 , Toshio Kurosaki 2 , Hisao Hamaguchi 2 , Hironori Harada 2 , Guliang Xia 6 , Yoshiaki Morita 1, 2 , Ichiro Aramori 1, 2 , Shuh Narumiya 1 , Shimon Sakaguchi 3, 4
Affiliation  

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:

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。
更新日期:2019-10-25
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