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The Bromodomain and Extra-Terminal Protein Inhibitor OTX015 Suppresses T Helper Cell Proliferation and Differentiation

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)594-601
Number of pages8
JournalCurrent Molecular Medicine
Volume18
Issue number9
DOIs
DateAccepted/In press - 20 Jan 2019
DatePublished (current) - 25 Jan 2019

Abstract

BACKGROUND: Dynamic epigenetic alterations accompanying CD4+ T helper cell differentiation have been implicated in multiple autoimmune diseases. The bromodomain and extra-terminal (BET) proteins are epigenetic regulators that recognize and bind to acetylated histones in chromatin and are targets for pharmacological inhibition. In this study we tested a new BET inhibitor under clinical development, OTX015, to interrogate its effects on key CD4+ T cell subsets associated with autoimmunity.

METHODS: Naïve and memory murine and human CD4+ T cells were isolated and differentiated into populations characterized by the expression of interferon (IFN)-γ and interleukin (IL)-17. Cultured cells were then exposed to varying concentrations of OTX015 in vitro, and its impact on cytokine expression was quantified by flow cytometry. In parallel, the expression of the transcription factors TBX21 and RORC was quantified by PCR. A previously studied BET inhibitor JQ1 was used as a pharmacological control.

RESULTS: OTX015 suppressed both murine and human CD4+ T cell proliferation. Its impact on cytokine expression varied in murine and human naïve and memory subsets. OTX015 was similarly effective as JQ1 in the suppression of cytokines and T helper cell proliferation. Higher concentrations of OTX015 also had a greater impact on the viability of murine versus human cells. IL-17 and IFN-γ expression was not altered in murine memory CD4+ T cells, whereas in human memory CD4+ T cells, OTX015 inhibited IL-17, but not IFN-γ. Across all human T cell subsets OTX015 suppressed IL-17 more effectively than IFN-γ.

CONCLUSION: Our studies demonstrate that OTX015 has anti-inflammatory effects by suppressing murine and human CD4+ T cell proliferation and subset-dependent proinflammatory cytokine expression, including the selective suppression of IL-17 in human memory CD4+ T cells.

Additional information

Print issue published in 2018

    Research areas

  • antiproliferation, Autoimmune disease, bromodomain and extraterminal domain (BET) inhibitors, CD4+ T cells, epigenetics, immunosuppression., OTX015

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  • Full-text PDF (accepted author manuscript)

    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via Bentham Science Publisher at http://www.eurekaselect.com/169393/article. Please refer to any applicable terms of use of the publisher.

    Accepted author manuscript, 292 KB, PDF-document

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  • Supplementary Figures 1 PDF

    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via Bentham Science Publisher at http://www.eurekaselect.com/169393/article. Please refer to any applicable terms of use of the publisher.

    Accepted author manuscript, 482 KB, PDF-document

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  • Supplementary Figures 2 PDF

    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via Bentham Science Publisher at http://www.eurekaselect.com/169393/article. Please refer to any applicable terms of use of the publisher.

    Accepted author manuscript, 488 KB, PDF-document

    Embargo ends: 25/01/20

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