Murine iNKT cells are depleted by liver damage via activation of P2RX7.
Acetaminophen
/ administration & dosage
Animals
Cells, Cultured
Chemical and Drug Induced Liver Injury
/ immunology
Disease Models, Animal
Humans
Immune Tolerance
Liver
/ pathology
Lymphocyte Activation
Mice
Mice, Inbred C57BL
Mice, Knockout
Natural Killer T-Cells
/ physiology
Receptors, Purinergic P2X7
/ genetics
NAD
NKT cells
P2RX7
Tissue-resident
liver
Journal
European journal of immunology
ISSN: 1521-4141
Titre abrégé: Eur J Immunol
Pays: Germany
ID NLM: 1273201
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
11
12
2019
revised:
21
03
2020
accepted:
05
05
2020
pubmed:
12
5
2020
medline:
12
1
2021
entrez:
12
5
2020
Statut:
ppublish
Résumé
Invariant natural killer T cells (iNKT) constitute up to 50% of liver lymphocytes and contribute to immunosurveillance as well as pathogenesis of the liver. Systemic activation of iNKT cells induces acute immune-mediated liver injury. However, how tissue damage events regulate iNKT cell function and homeostasis remains unclear. We found that specifically tissue-resident iNKT cells in liver and spleen express the tissue-damage receptor P2RX7 and the P2RX7-activating ectoenzyme ARTC2. P2RX7 expression restricted formation of iNKT cells in the liver suggesting that liver iNKT cells are actively restrained under homeostatic conditions. Deliberate activation of P2RX7 in vivo by exogenous NAD resulted in a nearly complete iNKT cell ablation in liver and spleen in a P2RX7-dependent manner. Tissue damage generated by acetaminophen-induced liver injury reduced the number of iNKT cells in the liver. The tissue-damage-induced iNKT cell depletion was driven by P2RX7 and localized to the site of injury, as iNKT cells in the spleen remained intact. The depleted liver iNKT cells reconstituted only slowly compared to other lymphocytes such as regulatory T cells. These findings suggest that tissue-damage-mediated depletion of iNKT cells acts as a feedback mechanism to limit iNKT cell-induced pathology resulting in the establishment of a tolerogenic environment.
Identifiants
pubmed: 32390174
doi: 10.1002/eji.201948509
doi:
Substances chimiques
P2rx7 protein, mouse
0
Receptors, Purinergic P2X7
0
Acetaminophen
362O9ITL9D
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1515-1524Subventions
Organisme : ZonMw
ID : 016.186.116
Pays : Netherlands
Organisme : ZonMw
ID : 917.13.338
Pays : Netherlands
Informations de copyright
© 2020 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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