HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Published online before print April 11, 2008

This Article Full Text (Reprint (PDF)) All Versions of this Article: jlb.0607352v1 84/1/264    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Biburger, M. Articles by Tiegs, G. Search for Related Content PubMed PubMed Citation Articles by Biburger, M. Articles by Tiegs, G.

© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0607352

Received for publication June 6, 2007.
Revised February 29, 2008.
Accepted for publication March 11, 2008.

Article

Activation-induced NKT cell hyporesponsiveness protects from -galactosylceramide hepatitis and is independent of active transregulatory factors

Markus Biburger ^* and Gisa Tiegs ^@

*Laboratory for Experimental Immunology and Immunotherapy, Nikolaus-Fiebiger-Center for Molecular Medicine, Medical Department III, University Hospital Erlangen, Germany; Department of Medicine I, Division of Experimental Immunology and Hepatology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany; and Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuremberg, Erlangen, Germany

^@ To whom correspondence should be addressed. E-mail: g.tiegs{at}uke.de.

	Abstract

NK T (NKT) cells, unique lymphocytes expressing features of NK and T lymphocytes, can specifically be activated with the glycolipid antigen -galactosylceramide (-GalCer). In humans and mice, this activation provokes pronounced cytokine responses. In C57BL/6 mice, -GalCer injection additionally induces NKT-mediated liver injury, representing a model for immune-mediated hepatitis in humans. However, a single -GalCer pretreatment of mice prevented NKT-mediated liver injury, cytokine responses (systemically and locally in the liver), and up-regulation of hepatocellular Fas upon -GalCer rechallenge. As -GalCer is used as a NKT cell-activating agent in clinical trials, an investigation of tolerance induction appears crucial. We demonstrate that -GalCer tolerance does not depend on Kupffer cells, IL-10, Caspase-3-mediated apoptosis, or CD4⁺CD25⁺ T regulatory cells (T_regs), which are crucial in other models of immunological tolerance. Amending relevant, earlier approaches of others, we cocultivated highly purified, nontolerized and tolerized liver NKT cells ex vivo and could convincingly exclude the relevance of transdominant NKT T_regs. These results strongly suggest -GalCer-induced tolerance to be exclusively caused by NKT cell intrinsic hyporesponsiveness. Tolerized mice showed specific diminishment of the intrahepatic CD4⁺ NKT cell subpopulation, with the CD4^– population largely unaffected, and revealed down-modulation of -GalCer-specific TCR and the NKT costimulator glucocorticoid-induced TNFR-related protein on liver NKT cells, whereas inhibitory Ly49I was increased. In conclusion, -GalCer tolerance could serve as a model for the frequently observed NKT cell hyporesponsiveness in tumor patients and might help to develop strategies for their reactivation. Conversely, approaches to render NKT cells hyporesponsive may constitute new therapeutic strategies for diseases, where aberrant NKT cell activation is causally involved.

Key Words: lymphocytes • natural killer T cells • tolerance • liver immunology • anergy • animal models