Conversion of antigen-specific effector/memory T cells into Foxp3-expressing Treg cells by inhibition of CDK8/19
2019
A promising way to restrain hazardous immune responses, such as
autoimmune diseaseand 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 naive CD4+ and CD8+ T cells. The induction was associated with
STAT5activation, 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 diseasein animal models. The results indicate that CDK8/19 is physiologically repressing
Foxp3expression in activated conventional T cells and that its pharmacological inhibition enables conversion of antigen-specific effector/
memory T cellsinto
Foxp3+ Treg cells for the treatment of various immunological diseases.
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