Regulatory T cells (Treg) are negative regulators of the immune response; however, it is poorly understood whether and how transcription is induced and regulated in the periphery during T-cell responses. Using -Timer of cell kinetics and activity (Tocky) mice, which report real-time expression we show that the flux of new expressors and the rate of transcription are increased during inflammation. These persistent dynamics of transcription determine the effector Treg programme and are dependent on a Foxp3 autoregulatory transcriptional circuit. Persistent 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 transcription, and we show proof of principle for the manipulation of dynamics by immunotherapy: new flux is promoted by anti-TNFRII antibody, and high-frequency expressors are targeted by anti-OX40 antibody. Collectively, our study dissects time-dependent mechanisms behind Foxp3-driven T-cell regulation and establishes the -Tocky system as a tool to investigate the mechanisms behind T-cell immunotherapies.
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| http://dx.doi.org/10.15252/embj.201899013 | DOI Listing |
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