Dissecting the Role of BET Bromodomain Proteins BRD2 and BRD4 in Human NK Cell Function
Natural killer (NK) cells are innate lymphocytes that play a pivotal role in the immune surveillance and elimination of transformed or virally infected cells. Using a chemo-genetic approach, we identify BET bromodomain containing proteins BRD2 and BRD4 as central regulators of NK cell functions, inc...
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doaj-27ac3bb7baf3417fb22ee808d526ef6c2021-02-26T13:10:00ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-02-011210.3389/fimmu.2021.626255626255Dissecting the Role of BET Bromodomain Proteins BRD2 and BRD4 in Human NK Cell FunctionAdam P. Cribbs0Panagis Filippakopoulos1Martin Philpott2Graham Wells3Henry Penn4Henrik Oerum5Viia Valge-Archer6Marc Feldmann7Udo Oppermann8Udo Oppermann9Udo Oppermann10Botnar Research Center, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, National Institute of Health Research Oxford Biomedical Research Unit (BRU), University of Oxford, Oxford, United KingdomStructural Genomics Consortium, University of Oxford, Oxford, United KingdomBotnar Research Center, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, National Institute of Health Research Oxford Biomedical Research Unit (BRU), University of Oxford, Oxford, United KingdomBotnar Research Center, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, National Institute of Health Research Oxford Biomedical Research Unit (BRU), University of Oxford, Oxford, United KingdomArthritis Centre, Northwick Park Hospital, Harrow, United KingdomRoche Innovation Center Copenhagen A/S, Hørsholm, DenmarkBioscience, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, United KingdomKennedy Institute of Rheumatology Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, Oxford, United KingdomBotnar Research Center, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, National Institute of Health Research Oxford Biomedical Research Unit (BRU), University of Oxford, Oxford, United KingdomFreiburg Institute of Advanced Studies, Freiburg, GermanyOxford Centre for Translational Myeloma Research, Oxford, United KingdomNatural killer (NK) cells are innate lymphocytes that play a pivotal role in the immune surveillance and elimination of transformed or virally infected cells. Using a chemo-genetic approach, we identify BET bromodomain containing proteins BRD2 and BRD4 as central regulators of NK cell functions, including direct cytokine secretion, NK cell contact-dependent inflammatory cytokine secretion from monocytes as well as NK cell cytolytic functions. We show that both BRD2 and BRD4 control inflammatory cytokine production in NK cells isolated from healthy volunteers and from rheumatoid arthritis patients. In contrast, knockdown of BRD4 but not of BRD2 impairs NK cell cytolytic responses, suggesting BRD4 as critical regulator of NK cell mediated tumor cell elimination. This is supported by pharmacological targeting where the first-generation pan-BET bromodomain inhibitor JQ1(+) displays anti-inflammatory effects and inhibit tumor cell eradication, while the novel bivalent BET bromodomain inhibitor AZD5153, which shows differential activity towards BET family members, does not. Given the important role of both cytokine-mediated inflammatory microenvironment and cytolytic NK cell activities in immune-oncology therapies, our findings present a compelling argument for further clinical investigation.https://www.frontiersin.org/articles/10.3389/fimmu.2021.626255/fullBET bromodomainBRD2BRD4NK cellepigenetics (DNA methylation histone modifications) |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Adam P. Cribbs Panagis Filippakopoulos Martin Philpott Graham Wells Henry Penn Henrik Oerum Viia Valge-Archer Marc Feldmann Udo Oppermann Udo Oppermann Udo Oppermann |
spellingShingle |
Adam P. Cribbs Panagis Filippakopoulos Martin Philpott Graham Wells Henry Penn Henrik Oerum Viia Valge-Archer Marc Feldmann Udo Oppermann Udo Oppermann Udo Oppermann Dissecting the Role of BET Bromodomain Proteins BRD2 and BRD4 in Human NK Cell Function Frontiers in Immunology BET bromodomain BRD2 BRD4 NK cell epigenetics (DNA methylation histone modifications) |
author_facet |
Adam P. Cribbs Panagis Filippakopoulos Martin Philpott Graham Wells Henry Penn Henrik Oerum Viia Valge-Archer Marc Feldmann Udo Oppermann Udo Oppermann Udo Oppermann |
author_sort |
Adam P. Cribbs |
title |
Dissecting the Role of BET Bromodomain Proteins BRD2 and BRD4 in Human NK Cell Function |
title_short |
Dissecting the Role of BET Bromodomain Proteins BRD2 and BRD4 in Human NK Cell Function |
title_full |
Dissecting the Role of BET Bromodomain Proteins BRD2 and BRD4 in Human NK Cell Function |
title_fullStr |
Dissecting the Role of BET Bromodomain Proteins BRD2 and BRD4 in Human NK Cell Function |
title_full_unstemmed |
Dissecting the Role of BET Bromodomain Proteins BRD2 and BRD4 in Human NK Cell Function |
title_sort |
dissecting the role of bet bromodomain proteins brd2 and brd4 in human nk cell function |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2021-02-01 |
description |
Natural killer (NK) cells are innate lymphocytes that play a pivotal role in the immune surveillance and elimination of transformed or virally infected cells. Using a chemo-genetic approach, we identify BET bromodomain containing proteins BRD2 and BRD4 as central regulators of NK cell functions, including direct cytokine secretion, NK cell contact-dependent inflammatory cytokine secretion from monocytes as well as NK cell cytolytic functions. We show that both BRD2 and BRD4 control inflammatory cytokine production in NK cells isolated from healthy volunteers and from rheumatoid arthritis patients. In contrast, knockdown of BRD4 but not of BRD2 impairs NK cell cytolytic responses, suggesting BRD4 as critical regulator of NK cell mediated tumor cell elimination. This is supported by pharmacological targeting where the first-generation pan-BET bromodomain inhibitor JQ1(+) displays anti-inflammatory effects and inhibit tumor cell eradication, while the novel bivalent BET bromodomain inhibitor AZD5153, which shows differential activity towards BET family members, does not. Given the important role of both cytokine-mediated inflammatory microenvironment and cytolytic NK cell activities in immune-oncology therapies, our findings present a compelling argument for further clinical investigation. |
topic |
BET bromodomain BRD2 BRD4 NK cell epigenetics (DNA methylation histone modifications) |
url |
https://www.frontiersin.org/articles/10.3389/fimmu.2021.626255/full |
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