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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 10.551 ) Pub Date : 2019-10-25 , DOI: 10.1126/sciimmunol.aaw2707
Masahiko Akamatsu, Norihisa Mikami, Naganari Ohkura, Ryoji Kawakami, Yohko Kitagawa, Atsushi Sugimoto, Keiji Hirota, Naoto Nakamura, Satoru Ujihara, Toshio Kurosaki, Hisao Hamaguchi, Hironori Harada, Guliang Xia, Yoshiaki Morita, Ichiro Aramori, Shuh Narumiya, Shimon Sakaguchi

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.
更新日期:2019-10-25

 

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