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

• Published in: The EMBO journal Vol. 37; no. 16
• Main Authors: Bending, David, Paduraru, Alina, Ducker, Catherine B, Prieto Martín, Paz, Crompton, Tessa, Ono, Masahiro
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.08.2018; Blackwell Publishing Ltd; John Wiley and Sons Inc
• Subjects: Animals; Antibodies - pharmacology; Cell differentiation; Circuits; CTLA-4 Antigen - genetics; CTLA-4 Antigen - immunology; Differentiation (biology); EMBO19; EMBO44; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - immunology; Foxp3; Foxp3 protein; Gene expression; Immune response; Immune system; Immunoregulation; Immunotherapy; Inflammation; Lymphocytes; Lymphocytes T; Mice; Mice, Transgenic; Proteins; Receptors, OX40 - antagonists & inhibitors; Receptors, OX40 - genetics; Receptors, OX40 - immunology; Receptors, Tumor Necrosis Factor, Type II - antagonists & inhibitors; Receptors, Tumor Necrosis Factor, Type II - genetics; Receptors, Tumor Necrosis Factor, Type II - immunology; Regulators; Ribonucleic acid; RNA; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - immunology; Time dependence; Tocky; Transcription; Transcription, Genetic - drug effects; Transcription, Genetic - genetics; Transcription, Genetic - immunology; transcriptional dynamics; Treg; Tumor necrosis factor; Foxp3; transcriptional dynamics; Tocky; immunotherapy; Treg
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.201899013

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. Synopsis Temporally‐persistent Foxp3 expression, established via a Foxp3‐protein dependent autoregulatory transcriptional circuit, drives effector regulatory T‐cell differentiation during inflammation. Foxp3 ‐Tocky mice reveal that Foxp3 transcription is highly dynamic in T‐cells in vivo . During inflammation, both the generation of new Foxp3 expressers and the rate of Foxp3 transcription in Treg increases. Temporally sustained Foxp3 transcription induces effector Treg differentiation through a Foxp3‐protein driven autoregulatory transcriptional loop. Foxp3 ‐Tocky can reveal mechanism of action behind immunotherapies. Graphical Abstract A novel mouse model allows to track the kinetic and temporal aspects of Foxp3 expression in regulatory T cells during inflammation, showing that Treg development depends on persistent Foxp3 transcription.