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A temporally dynamic Foxp3 autoregulatory transcriptional circuit controls the effector Treg programme

Bending, D; Paduraru, A; Ducker, CB; Martin, PP; Crompton, T; Ono, M; (2018) A temporally dynamic Foxp3 autoregulatory transcriptional circuit controls the effector Treg programme. The EMBO Journal , 37 (16) , Article e99013. 10.15252/embj.201899013. Green open access

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Abstract

Regulatory T cells (Treg) are negative regulators of the immune response; however, it is poorly understood whether and how Foxp3 transcription is induced and regulated in the periphery during T‐cell responses. Using Foxp3‐Timer of cell kinetics and activity (Tocky) mice, which report real‐time Foxp3 expression, we show that the flux of new Foxp3 expressors and the rate of Foxp3 transcription are increased during inflammation. These persistent dynamics of Foxp3 transcription determine the effector Treg programme and are dependent on a Foxp3 autoregulatory transcriptional circuit. Persistent Foxp3 transcriptional activity controls the expression of coinhibitory molecules, including CTLA‐4 and effector Treg signature genes. Using RNA‐seq, we identify two groups of surface proteins based on their relationship to the temporal dynamics of Foxp3 transcription, and we show proof of principle for the manipulation of Foxp3 dynamics by immunotherapy: new Foxp3 flux is promoted by anti‐TNFRII antibody, and high‐frequency Foxp3 expressors are targeted by anti‐OX40 antibody. Collectively, our study dissects time‐dependent mechanisms behind Foxp3‐driven T‐cell regulation and establishes the Foxp3‐Tocky system as a tool to investigate the mechanisms behind T‐cell immunotherapies.

Type: Article
Title: A temporally dynamic Foxp3 autoregulatory transcriptional circuit controls the effector Treg programme
Open access status: An open access version is available from UCL Discovery
DOI: 10.15252/embj.201899013
Publisher version: https://doi.org/10.15252/embj.201899013
Language: English
Additional information: © 2018 The Authors. Published under the terms of the CC BY 4.0 license (https://creativecommons.org/licenses/by/4.0/).
Keywords: Foxp3, immunotherapy, Tocky, transcriptional dynamics, Treg
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10060367
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