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
  • 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. [email protected] [email protected].
  • 8. Department of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Yamadaoka, Suita, Osaka 565-0871, Japan. [email protected] [email protected].
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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