DCA promotes a novel tolerogenic program in CD4+ T cells by inhibiting CDK8
Keagan G Moo,
Kaitlin J. Flynn,
Thomas B Sundberg,
Alykhan F Shamji,
Nathanael S. Gray,
Vivian H Gersuk,
David E Levy,
Isabelle J Marié,
Ziaur S Rahman,
Peter S. Linsley,
Ramnik J. Xavier,
Posted 03 Dec 2019
bioRxiv DOI: 10.1101/855429
Posted 03 Dec 2019
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.
- Downloaded 200 times
- Download rankings, all-time:
- Site-wide: 65,894 out of 84,908
- In immunology: 1,733 out of 2,384
- Year to date:
- Site-wide: 26,085 out of 84,908
- Since beginning of last month:
- Site-wide: 22,813 out of 84,908
Downloads over time
Distribution of downloads per paper, site-wide
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!