Natural killer T cell dysfunction in CD39-null mice protects against concanavalin A-induced hepatitis

Beldi, Guido; Wu, Yan; Banz, Yara; Nowak, Michael; Miller, Lindsay; Enjyoji, Keiichi; Haschemi, Arvand; Yegutkin, Gennady G; Candinas, Daniel; Exley, Mark; Robson, Simon C (2008). Natural killer T cell dysfunction in CD39-null mice protects against concanavalin A-induced hepatitis. Hepatology, 48(3), pp. 841-52. Hoboken, N.J.: Wiley Interscience 10.1002/hep.22401

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Concanavalin A (Con A)-induced injury is an established natural killer T (NKT) cell-mediated model of inflammation that has been used in studies of immune liver disease. Extracellular nucleotides, such as adenosine triphosphate, are released by Con A-stimulated cells and bind to specific purinergic type 2 receptors to modulate immune activation responses. Levels of extracellular nucleotides are in turn closely regulated by ectonucleotidases, such as CD39/NTPDase1. Effects of extracellular nucleotides and CD39 on NKT cell activation and upon hepatic inflammation have been largely unexplored to date. Here, we show that NKT cells express both CD39 and CD73/ecto-5'-nucleotidase and can therefore generate adenosine from extracellular nucleotides, whereas natural killer cells do not express CD73. In vivo, mice null for CD39 are protected from Con A-induced liver injury and show substantively lower serum levels of interleukin-4 and interferon-gamma when compared with matched wild-type mice. Numbers of hepatic NKT cells are significantly decreased in CD39 null mice after Con A administration. Hepatic NKT cells express most P2X and P2Y receptors; exceptions include P2X3 and P2Y11. Heightened levels of apoptosis of CD39 null NKT cells in vivo and in vitro appear to be driven by unimpeded activation of the P2X7 receptor. CONCLUSION: CD39 and CD73 are novel phenotypic markers of NKT cells. Deletion of CD39 modulates nucleotide-mediated cytokine production by, and limits apoptosis of, hepatic NKT cells providing protection against Con A-induced hepatitis. This study illustrates a further role for purinergic signaling in NKT-mediated mechanisms that result in liver immune injury.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Visceral Surgery 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Mu50 > Forschungsgruppe Herz und Gefässe
UniBE Contributor:	Beldi, Guido Jakob Friedrich, Banz Wälti, Yara Sarah, Candinas, Daniel
ISSN:	0270-9139
ISBN:	18752325
Publisher:	Wiley Interscience
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 15:06
Last Modified:	02 Mar 2023 23:23
Publisher DOI:	10.1002/hep.22401
PubMed ID:	18752325
Web of Science ID:	000258942100017
URI:	https://boris.unibe.ch/id/eprint/28548 (FactScience: 121275)