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.