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Immune health requires innate and adaptive immune cells to engage precisely balanced pro- and anti-inflammatory forces. A holistic understanding of how individual small molecules affect this balance is essential to anticipate immune-related side effects, select mitigating immunomodulatory therapies and highlight novel utility as immunomodulators. We previously showed that the high-specificity, low-toxicity cyclin dependent kinase 8 (CDK8) inhibitor DCA promotes tolerogenic effects in innate immune cells. Here, we demonstrate that DCA exerts a novel profile of tolerogenic activity on CD4+ T cells, promoting Treg and Th2 while inhibiting Th1 and Th17 differentiation. DCA enhances human Treg differentiation and our models demonstrate clear tolerogenic function of DCA-driven Tregs in the absence of confounding contribution from DCA-innate immune interactions. DCA engages unique mechanisms, including specifically enhancing early Foxp3 expression via regulating c-Jun phosphorylation, to promote Treg differentiation. CDK8 inhibitors are currently being developed to treat cancer; our findings suggest that the potential blunting of host-versus-tumor effects may warrant ancillary pro-inflammatory agents. Importantly, these results highlight novel utility of DCA as an immunomodulator, not only in vivo, but also in ex vivo cellular therapy.

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