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Nur77-Tempo mice reveal T cell steady state antigen recognition.

作者信息

Elliot Thomas A E, Jennings Emma K, Lecky David A J, Rouvray Sophie, Mackie Gillian M, Scarfe Lisa, Sheriff Lozan, Ono Masahiro, Maslowski Kendle M, Bending David

机构信息

Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.

Department of Life Sciences, Imperial College London, London, SW7 2AZ, UK.

出版信息

Discov Immunol. 2022 Dec 22;1(1):kyac009. doi: 10.1093/discim/kyac009.


DOI:10.1093/discim/kyac009
PMID:36704407
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7614040/
Abstract

In lymphocytes, gene expression is specifically regulated by antigen receptor signalling, making them ideal targets for use as distal T cell receptor (TCR) reporters. -Timer of cell kinetics and activity (Tocky) mice are a ground-breaking tool to report TCR-driven expression using Fluorescent Timer protein (FT). FT undergoes a time-dependent shift in its emission spectrum following translation, allowing for the temporal reporting of transcriptional events. Our recent work suggested that /Nur77 may be a more sensitive gene to distal TCR signals compared to , so we, therefore, generated Nur77-Timer-rapidly-expressed-in-lymphocytes (Tempo) mice that express FT under the regulation of Nur77. We validated the ability of Nur77-Tempo mice to report TCR and B cell receptor signals and investigated the signals regulating Nur77-FT expression. We found that Nur77-FT was sensitive to low-strength TCR signals, and its brightness was graded in response to TCR signal strength. Nur77-FT detected positive selection signals in the thymus, and analysis of FT expression revealed that positive selection signals are often persistent in nature, with most thymic Treg expressing FT Blue. We found that active TCR signals in the spleen are low frequency, but CD69 lymphoid T cells are enriched for FT Blue Red T cells, suggesting frequent TCR signalling. In non-lymphoid tissue, we saw a dissociation of FT protein from CD69 expression, indicating that tissue residency is not associated with tonic TCR signals. Nur77-Tempo mice, therefore, combine the temporal dynamics from the Tocky innovation with increased sensitivity of to lower TCR signal strengths.

摘要
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df32/10917201/437e6cfecbd6/kyac009_fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df32/10917201/ad198c846ffd/kyac009_fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df32/10917201/5a72447a8d44/kyac009_fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df32/10917201/914c87ea5890/kyac009_fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df32/10917201/437e6cfecbd6/kyac009_fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df32/10917201/ad198c846ffd/kyac009_fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df32/10917201/5a72447a8d44/kyac009_fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df32/10917201/914c87ea5890/kyac009_fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/df32/10917201/437e6cfecbd6/kyac009_fig3.jpg

相似文献

[1]
Nur77-Tempo mice reveal T cell steady state antigen recognition.

Discov Immunol. 2022-12-22

[2]
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[3]
A timer for analyzing temporally dynamic changes in transcription during differentiation in vivo.

J Cell Biol. 2018-6-25

[4]
Strong Basal/Tonic TCR Signals Are Associated with Negative Regulation of Naive CD4 T Cells.

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[5]
Cbl-b mitigates the responsiveness of naive CD8 T cells that experience extensive tonic T cell receptor signaling.

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[6]
Unraveling T-cell dynamics using fluorescent timer: Insights from the Tocky system.

Biophys Physicobiol. 2024-2-16

[7]
Inhibition of Nur77/Nurr1 leads to inefficient clonal deletion of self-reactive T cells.

J Exp Med. 1996-4-1

[8]
Positive and negative thymic selection in T cell receptor-transgenic mice correlate with Nur77 mRNA expression.

Eur J Immunol. 1997-8

[9]
Adaptation by naïve CD4 T cells to self-antigen-dependent TCR signaling induces functional heterogeneity and tolerance.

Proc Natl Acad Sci U S A. 2019-7-8

[10]
Higher Sensitivity of Foxp3+ Treg Compared to Foxp3- Conventional T Cells to TCR-Independent Signals for CD69 Induction.

PLoS One. 2015-9-9

引用本文的文献

[1]
Conserved developmental rewiring of the TCR signalosome drives tolerance in innate-like lymphocytes.

bioRxiv. 2025-5-13

[2]
Lag3 and PD-1 pathways preferentially regulate NFAT-dependent TCR signalling programmes during early CD4 T cell activation.

Immunother Adv. 2025-3-28

[3]
Interferon-γ and IL-27 positively regulate type 1 regulatory T cell development during adaptive tolerance.

iScience. 2025-3-28

[4]
TockyPrep: data preprocessing methods for flow cytometric fluorescent timer analysis.

BMC Bioinformatics. 2025-2-8

[5]
Stem-like memory and precursors of exhausted T cells share a common progenitor defined by ID3 expression.

Sci Immunol. 2025-1-31

[6]
Nr4a1 and Nr4a3 redundantly control clonal deletion and contribute to an anergy-like transcriptome in auto-reactive thymocytes to impose tolerance in mice.

Nat Commun. 2025-1-17

[7]
Salmonella cancer therapy metabolically disrupts tumours at the collateral cost of T cell immunity.

EMBO Mol Med. 2024-12

[8]
Type I IFN Induces TCR-dependent and -independent Antimicrobial Responses in γδ Intraepithelial Lymphocytes.

J Immunol. 2024-11-1

[9]
Unraveling T-cell dynamics using fluorescent timer: Insights from the Tocky system.

Biophys Physicobiol. 2024-2-16

[10]
Time-resolved role of P2X4 and P2X7 during CD8 T cell activation.

Front Immunol. 2024

本文引用的文献

[1]
Heterogeneity of tissue resident memory T cells.

Immunol Lett. 2022-5

[2]
Antigen and checkpoint receptor engagement recalibrates T cell receptor signal strength.

Immunity. 2021-11-9

[3]
Tissue environment, not ontogeny, defines murine intestinal intraepithelial T lymphocytes.

Elife. 2021-9-2

[4]
Hierarchy of signaling thresholds downstream of the T cell receptor and the Tec kinase ITK.

Proc Natl Acad Sci U S A. 2021-8-31

[5]
Discrete tissue microenvironments instruct diversity in resident memory T cell function and plasticity.

Nat Immunol. 2021-9

[6]
Application of dual -GFP -Tocky reporter mice to study T cell receptor signaling by flow cytometry.

STAR Protoc. 2021-3-19

[7]
Nr4a1 and Nr4a3 Reporter Mice Are Differentially Sensitive to T Cell Receptor Signal Strength and Duration.

Cell Rep. 2020-11-3

[8]
TCR Signal Strength and Antigen Affinity Regulate CD8 Memory T Cells.

J Immunol. 2020-9-1

[9]
Tissue-resident memory T cell reactivation by diverse antigen-presenting cells imparts distinct functional responses.

J Exp Med. 2020-8-3

[10]
Isolation, Characterization, and Culture of Intestinal Intraepithelial Lymphocytes.

Methods Mol Biol. 2020

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