Research ArticleIMMUNE REGULATION

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

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Science Immunology  25 Oct 2019:
Vol. 4, Issue 40, eaaw2707
DOI: 10.1126/sciimmunol.aaw2707

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Pharmacological retraining for T cells

Regulatory T (Treg) cells expressing the Foxp3 transcription factor play a critical role in dampening overactive immune responses including autoimmune diseases. Akamatsu et al. screened a library of small molecules and identified a compound that promotes Treg differentiation on the basis of its ability to inhibit the cyclin-dependent kinases CDK8 and CDK19. The Treg-promoting activity of the CDK8/19 inhibitor did not require transforming growth factor–β (TGF-β) and reduced disease activity in mouse models of autoimmune diabetes and encephalomyelitis. These findings indicate that CDK8/19 inhibitors are a new class of immunomodulatory drugs capable of generating Treg cells with potential clinical applications in promoting tolerance and squelching autoimmunity.

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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