Conversion of antigen-specific effector/memory T cells into Foxp3-expressing T reg cells by inhibition of CDK8/19

• Published in: Science immunology Vol. 4; no. 40
• Main Authors: Akamatsu, Masahiko, Mikami, Norihisa, Ohkura, Naganari, Kawakami, Ryoji, Kitagawa, Yohko, Sugimoto, Atsushi, Hirota, Keiji, Nakamura, Naoto, Ujihara, Satoru, Kurosaki, Toshio, Hamaguchi, Hisao, Harada, Hironori, Xia, Guliang, Morita, Yoshiaki, Aramori, Ichiro, Narumiya, Shuh, Sakaguchi, Shimon
• Format: Journal Article
• Language: English
• Published: United States 25.10.2019
• ISSN: 2470-9468
• DOI: 10.1126/sciimmunol.aaw2707

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 (T ) 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 T 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 T 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 T cells for the treatment of various immunological diseases.