Autoimmune, Cholestatic and Biliary Disease
Article first published online: 2 MAY 2008
Copyright © 2008 American Association for the Study of Liver Diseases
Volume 48, Issue 3, pages 841–852, September 2008
How to Cite
Beldi, G., Wu, Y., Banz, Y., Nowak, M., Miller, L., Enjyoji, K., Haschemi, A., Yegutkin, G. G., Candinas, D., Exley, M. and Robson, S. C. (2008), Natural killer T cell dysfunction in CD39-null mice protects against concanavalin A–induced hepatitis. Hepatology, 48: 841–852. doi: 10.1002/hep.22401
This work was presented in part at Digestive Diseases Week, Washington, DC, May 17-22, 2007.
Potential conflict of interest: Nothing to report.
- Issue published online: 27 AUG 2008
- Article first published online: 2 MAY 2008
- Accepted manuscript online: 2 MAY 2008 12:00AM EST
- Manuscript Accepted: 21 APR 2008
- Manuscript Received: 3 SEP 2007
- National Institutes of Health. Grant Numbers: HL57307, HL63972, HL076540
- Swiss National Research Foundation. Grant Numbers: PASMA-115700, PBBEB-112764, DK 066917
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-γ 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. (HEPATOLOGY 2008.)