2. Academic Validation
  3. Conversion of antigen-specific effector/memory T cells into Foxp3-expressing Treg cells by inhibition of CDK8/19

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

  • Sci Immunol. 2019 Oct 25;4(40):eaaw2707. 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 7,  Shimon Sakaguchi 8 4
Affiliations

Affiliations

  • 1 Center for Innovation in Immunoregulation Technology and Therapeutics, Kyoto University Graduate School of Medicine, Konoe-cho Yoshida, Sakyo-ku, Kyoto, Kyoto 606-8501, Japan.
  • 2 Drug Discovery Research, Astellas Pharma Inc., Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
  • 3 Department of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Yamadaoka, Suita, Osaka 565-0871, Japan.
  • 4 Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Kyoto 606-8507, Japan.
  • 5 Department of Frontier Research in Tumor Immunology, Center of Medical Innovation and Translational Research, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
  • 6 Astellas Research Institute of America, Skokie, IL 60077, USA.
  • 7 Center for Innovation in Immunoregulation Technology and Therapeutics, Kyoto University Graduate School of Medicine, Konoe-cho Yoshida, Sakyo-ku, Kyoto, Kyoto 606-8501, Japan. snaru@mfour.med.kyoto-u.ac.jp shimon@ifrec.osaka-u.ac.jp.
  • 8 Department of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Yamadaoka, Suita, Osaka 565-0871, Japan. snaru@mfour.med.kyoto-u.ac.jp shimon@ifrec.osaka-u.ac.jp.
PMID: 31653719 DOI: 10.1126/sciimmunol.aaw2707
Abstract

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.

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