A temporally dynamic Foxp3 autoregulatory transcriptional circuit controls the effector Treg programme
File(s)
Published version
Author(s)
Type
Journal Article
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.
Date Issued
2018-08-15
Date Acceptance
2018-06-12
Citation
The EMBO Journal, 2018, 37 (16)
ISSN
0261-4189
Publisher
EMBO Press
Journal / Book Title
The EMBO Journal
Volume
37
Issue
16
Copyright Statement
© 2018 The Authors. Published under the terms of the CC BY
4.0 license (https://creativecommons.org/licenses/by/4.0/).
4.0 license (https://creativecommons.org/licenses/by/4.0/).
Sponsor
Biotechnology and Biological Sciences Research Council
Biotechnology and Biological Sciences Research Council (BBSRC)
Grant Number
BB/J013951/1
BB/J013951/2
Subjects
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
Foxp3
immunotherapy
Tocky
transcriptional dynamics
Treg
REGULATORY T-CELLS
EXPRESSION
RECEPTOR
DIFFERENTIATION
COSTIMULATION
AFFINITY
COMPLEX
ROLES
GENE
OX40
Foxp3
Tocky
Treg
immunotherapy
transcriptional dynamics
Animals
Antibodies
CTLA-4 Antigen
Forkhead Transcription Factors
Mice
Mice, Transgenic
Receptors, OX40
Receptors, Tumor Necrosis Factor, Type II
T-Lymphocytes, Regulatory
Transcription, Genetic
Animals
Mice, Transgenic
Mice
Receptors, Tumor Necrosis Factor, Type II
Antibodies
Transcription, Genetic
T-Lymphocytes, Regulatory
Forkhead Transcription Factors
Receptors, OX40
CTLA-4 Antigen
06 Biological Sciences
08 Information and Computing Sciences
11 Medical and Health Sciences
Developmental Biology
Publication Status
Published
Article Number
e99013
Date Publish Online
2018-07-10