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

Authors

  • Guido Beldi,

    1. Liver and Transplantation Centers, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
    2. Department of Visceral and Transplant Surgery, Inselspital, University Hospital, Bern, Switzerland
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  • Yan Wu,

    1. Liver and Transplantation Centers, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
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  • Yara Banz,

    1. Liver and Transplantation Centers, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
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  • Michael Nowak,

    1. Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
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  • Lindsay Miller,

    1. Liver and Transplantation Centers, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
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  • Keiichi Enjyoji,

    1. Liver and Transplantation Centers, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
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  • Arvand Haschemi,

    1. Liver and Transplantation Centers, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
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  • Gennady G. Yegutkin,

    1. MediCity Research Laboratory, University of Turku, National Public Health Institute, Turku, Finland
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  • Daniel Candinas,

    1. Department of Visceral and Transplant Surgery, Inselspital, University Hospital, Bern, Switzerland
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  • Mark Exley,

    1. Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
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  • Simon C. Robson

    Corresponding author
    1. Liver and Transplantation Centers, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
    • Liver and Transplantation Centers, Room 301, Research North, Beth Israel Deaconess Medical Center, 99 Brookline Avenue, Boston, MA 02215
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    • fax: 617-632-1861


  • This work was presented in part at Digestive Diseases Week, Washington, DC, May 17-22, 2007.

  • Potential conflict of interest: Nothing to report.

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.)

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