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.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens / immunology
  • CD4-Positive T-Lymphocytes / immunology*
  • Cells, Cultured
  • Cyclin-Dependent Kinase 8 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 8 / deficiency
  • Cyclin-Dependent Kinase 8 / immunology
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • Cyclin-Dependent Kinases / deficiency
  • Cyclin-Dependent Kinases / immunology
  • Forkhead Transcription Factors / genetics*
  • Forkhead Transcription Factors / immunology
  • Immunologic Memory / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, Transgenic
  • Protein Kinase Inhibitors / pharmacology*
  • Pyridines / pharmacology*
  • Pyrimidines / pharmacology*
  • T-Lymphocytes, Regulatory / immunology*


  • Antigens
  • Chir 99021
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Protein Kinase Inhibitors
  • Pyridines
  • Pyrimidines
  • CDK19 protein, mouse
  • Cdk8 protein, mouse
  • Cyclin-Dependent Kinase 8
  • Cyclin-Dependent Kinases