Nr4a1 and Nr4a3 Reporter Mice Are Differentially Sensitive to T Cell Receptor Signal Strength and Duration.
Animals
CD4-Positive T-Lymphocytes
/ immunology
CD8-Positive T-Lymphocytes
/ immunology
Calcineurin
/ metabolism
DNA-Binding Proteins
/ metabolism
Female
Genes, Reporter
Green Fluorescent Proteins
/ metabolism
MAP Kinase Signaling System
Male
Mice, Inbred C57BL
Mice, Transgenic
NFATC Transcription Factors
/ metabolism
Nerve Tissue Proteins
/ metabolism
Nuclear Receptor Subfamily 4, Group A, Member 1
/ metabolism
Peptides
/ metabolism
Receptors, Antigen, T-Cell
/ metabolism
Receptors, Steroid
/ metabolism
Receptors, Thyroid Hormone
/ metabolism
Signal Transduction
NFAT
Nr4a1-GFP
Nr4a3-Tocky
T cell activation
T cell development
T cell receptor signaling
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
03 11 2020
03 11 2020
Historique:
received:
07
10
2019
revised:
07
08
2020
accepted:
08
10
2020
entrez:
4
11
2020
pubmed:
5
11
2020
medline:
8
5
2021
Statut:
ppublish
Résumé
Nr4a receptors are activated by T cell receptor (TCR) signaling and play key roles in T cell differentiation. Which TCR signaling pathways regulate Nr4a receptors and their sensitivities to TCR signal strength and duration remains unclear. Using Nr4a1/Nur77-GFP and Nr4a3-Timer of cell kinetics and activity (Tocky) mice, we elucidate the signaling pathways governing Nr4a receptor expression. We reveal that Nr4a1-Nr4a3 are Src family kinase dependent. Moreover, Nr4a2 and Nr4a3 are attenuated by calcineurin inhibitors and bind nuclear factor of activated T cells 1 (NFAT1), highlighting a necessary and sufficient role for NFAT1 in the control of Nr4a2 and Nr4a3, but redundancy for Nr4a1. Nr4a1-GFP is activated by tonic and cognate signals during T cell development, whereas Nr4a3-Tocky requires cognate peptide:major histocompatibility complex (MHC) interactions for expression. Compared to Nr4a3-Tocky, Nr4a1-GFP is approximately 2- to 3-fold more sensitive to TCR signaling and is detectable by shorter periods of TCR signaling. These findings suggest that TCR signal duration may be an underappreciated aspect influencing the developmental fate of T cells in vivo.
Identifiants
pubmed: 33147449
pii: S2211-1247(20)31317-6
doi: 10.1016/j.celrep.2020.108328
pmc: PMC7653457
pii:
doi:
Substances chimiques
DNA-Binding Proteins
0
NFATC Transcription Factors
0
Nerve Tissue Proteins
0
Nr4a1 protein, mouse
0
Nr4a3 protein, mouse
0
Nuclear Receptor Subfamily 4, Group A, Member 1
0
Peptides
0
Receptors, Antigen, T-Cell
0
Receptors, Steroid
0
Receptors, Thyroid Hormone
0
Green Fluorescent Proteins
147336-22-9
Calcineurin
EC 3.1.3.16
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
108328Subventions
Organisme : Medical Research Council
ID : MR/N000919/1
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/J013951/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 214018/Z/18/Z
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/S003800/1
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.
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