The Cyclin-Dependent Kinase 8 (CDK8) Inhibitor DCA Promotes a Tolerogenic Chemical Immunophenotype in CD4⁺ T Cells via a Novel CDK8-GATA3-FOXP3 Pathway

ABSTRACT

Immune health requires innate and adaptive immune cells to engage precisely balanced pro- and anti-inflammatory forces. We employ the concept of chemical immunophenotypes to classify small molecules functionally or mechanistically according to their patterns of effects on primary innate and adaptive immune cells. The high-specificity, low-toxicity cyclin-dependent kinase 8 (CDK8) inhibitor 16-didehydro-cortistatin A (DCA) exerts a distinct tolerogenic profile in both innate and adaptive immune cells. DCA promotes regulatory T cells (T_reg) and Th2 differentiation while inhibiting Th1 and Th17 differentiation in both murine and human cells. This unique chemical immunophenotype led to mechanistic studies showing that DCA promotes T_reg differentiation in part by regulating a previously undescribed CDK8-GATA3-FOXP3 pathway that regulates early pathways of Foxp3 expression. These results highlight previously unappreciated links between T_reg and Th2 differentiation and extend our understanding of the transcription factors that regulate T_reg differentiation and their temporal sequencing. These findings have significant implications for future mechanistic and translational studies of CDK8 and CDK8 inhibitors.

KEYWORDS:

• CDK8
• GATA3
• T cell differentiation
• T cells
• cyclin-dependent kinases

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SUPPLEMENTAL MATERIAL

Supplemental material is available online only.

ACKNOWLEDGMENTS

We express our deep appreciation to Anne Hocking, Karen Cerosaletti, Jessica Hamerman, and Daniel Campbell for helpful discussion. B10.Rag2^−/− mice were a kind gift from Brian Kelsall. We acknowledge Tina Polintan for editorial assistance.

B.K. was supported by N.I.H. grant number K08 DK104021. Acquisition of key equipment was made possible by support from the Murdock Foundation.

B.K., A.A., R.J.X., P.S.L., V.H.G., and T.B.S. designed studies. A.A., K.G.M., K.J.F., T.B.S., L.J., A.F.S., and B.K. conducted experiments. A.A., K.J.F., K.G.M., Y.Z., and B.K. analyzed data. N.S.G., T.B.S., T.D., Y.Z., D.E.L., I.J.M., and Z.S.R. provided reagents. A.A. and B.K. wrote the manuscript.

We have no conflicts of interest to disclose.