miR-181a/b-1 controls thymic selection of Treg cells and tunes their suppressive capacity.
Journal
PLoS biology
ISSN: 1545-7885
Titre abrégé: PLoS Biol
Pays: United States
ID NLM: 101183755
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
18
05
2018
accepted:
27
02
2019
revised:
21
03
2019
pubmed:
12
3
2019
medline:
26
11
2019
entrez:
12
3
2019
Statut:
epublish
Résumé
The interdependence of selective cues during development of regulatory T cells (Treg cells) in the thymus and their suppressive function remains incompletely understood. Here, we analyzed this interdependence by taking advantage of highly dynamic changes in expression of microRNA 181 family members miR-181a-1 and miR-181b-1 (miR-181a/b-1) during late T-cell development with very high levels of expression during thymocyte selection, followed by massive down-regulation in the periphery. Loss of miR-181a/b-1 resulted in inefficient de novo generation of Treg cells in the thymus but simultaneously permitted homeostatic expansion in the periphery in the absence of competition. Modulation of T-cell receptor (TCR) signal strength in vivo indicated that miR-181a/b-1 controlled Treg-cell formation via establishing adequate signaling thresholds. Unexpectedly, miR-181a/b-1-deficient Treg cells displayed elevated suppressive capacity in vivo, in line with elevated levels of cytotoxic T-lymphocyte-associated 4 (CTLA-4) protein, but not mRNA, in thymic and peripheral Treg cells. Therefore, we propose that intrathymic miR-181a/b-1 controls development of Treg cells and imposes a developmental legacy on their peripheral function.
Identifiants
pubmed: 30856173
doi: 10.1371/journal.pbio.2006716
pii: pbio.2006716
pmc: PMC6428341
doi:
Substances chimiques
MicroRNAs
0
Nr4a1 protein, mouse
0
Nr4a2 protein, mouse
0
Nuclear Receptor Subfamily 4, Group A, Member 1
0
Nuclear Receptor Subfamily 4, Group A, Member 2
0
mirn181 microRNA, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e2006716Subventions
Organisme : Cancer Research UK
ID : FC001092
Pays : United Kingdom
Organisme : Wellcome Trust
ID : FC001092
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UP_1202/11
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 205014/Z/16/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : FC001092
Pays : United Kingdom
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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