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

David Bending, Alina Paduraru, Catherine Ducker, Paz Prieto Martin, Tessa Crompton, Masahiro Ono

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)
210 Downloads (Pure)

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.
Original languageEnglish
Article numbere99013
Number of pages16
JournalThe EMBO journal
Volume37
Issue number16
Early online date10 Jul 2018
DOIs
Publication statusPublished - 15 Aug 2018

Keywords

  • Foxp3
  • Immunotherapy
  • Tocky
  • Transcriptional Dynamics
  • Treg

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