Natural killer T cell dysfunction in CD39-null mice protects against concanavalin A-induced hepatitis
Open Access
- 2 May 2008
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Journal of Hepatology
- Vol. 48 (3), 841-852
- https://doi.org/10.1002/hep.22401
Abstract
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.)This publication has 47 references indexed in Scilit:
- Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppressionThe Journal of Experimental Medicine, 2007
- Adenosine A2A receptor activation reduces hepatic ischemia reperfusion injury by inhibiting CD1d-dependent NKT cell activationThe Journal of Experimental Medicine, 2006
- The Detection of Micromolar Pericellular ATP Pool on Lymphocyte Surface by Using Lymphoid Ecto-Adenylate Kinase as Intrinsic ATP SensorMolecular Biology of the Cell, 2006
- Glycolipid α-C-galactosylceramide is a distinct inducer of dendritic cell function during innate and adaptive immune responses of miceProceedings of the National Academy of Sciences of the United States of America, 2006
- Interleukin-15 prevents concanavalin A-induced liver injury in mice via NKT cell-dependent mechanismJournal of Hepatology, 2006
- To be or not to be NKT: Natural killer T cells in the liverJournal of Hepatology, 2004
- A Monoclonal Antibody to the α2 Domain of Murine Major Histocompatibility Complex Class I that Specifically Kills Activated Lymphocytes and Blocks Liver Damage in the Concanavalin A Hepatitis ModelThe Journal of Experimental Medicine, 2003
- Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damageNature, 2001
- Importance of Kupffer Cells for T-Cell-Dependent Liver Injury in MiceThe American Journal of Pathology, 2000
- The purinergic P2Z receptor of human macrophage cells. Characterization and possible physiological role.JCI Insight, 1995