SEARCH:   Advanced

Blood, 15 November 2008, Vol. 112, No. 10, pp. 4128-4138. Prepublished online as a Blood First Edition Paper on September 8, 2008; DOI 10.1182/blood-2008-05-157529. This Article Full Text Full Text (PDF) Supplementary Figures and Videos All Versions of this Article: blood-2008-05-157529v1 112/10/4128    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Wang, X. Articles by Gumperz, J. E. Search for Related Content PubMed PubMed Citation Articles by Wang, X. Articles by Gumperz, J. E. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Natural killer T-cell autoreactivity leads to a specialized activation state Xiaohua Wang1, Xiuxu Chen1, Lance Rodenkirch2, William Simonson1, Sarah Wernimont1, Rachel M. Ndonye3, Natacha Veerapen4, Darren Gibson5, Amy R. Howell3, Gurdyal S. Besra4, Gavin F. Painter5, Anna Huttenlocher1, and Jenny E. Gumperz1 1 Department of Medical Microbiology and Immunology, and 2 W. M. Keck Lab for Biological Imaging, University of Wisconsin School of Medicine and Public Health, Madison; 3 Department of Chemistry, University of Connecticut, Storrs; 4 School of Biosciences, University of Birmingham, Edgbaston, United Kingdom; and 5 Carbohydrate Chemistry Team, Industrial Research, Lower Hutt, New Zealand Natural killer T (NKT) cells are innate-like T cells that recognize specific microbial antigens and also display autoreactivity to self-antigens. The nature of NKT-cell autoreactive activation remains poorly understood. We show here that the mitogen-activated protein kinase (MAPK) pathway is operative during human NKT-cell autoreactive activation, but calcium signaling is severely impaired. This results in a response that is biased toward granulocyte macrophage colony-stimulating factor (GM-CSF) secretion because this cytokine requires extracellular signal-regulated kinase (ERK) signaling but is not highly calcium dependent, whereas interferon- (IFN-), interleukin (IL)–4, and IL-2 production are minimal. Autoreactive activation was associated with reduced migration velocity but did not induce arrest; thus, NKT cells retained the ability to survey antigen presenting cells (APCs). IL-12 and IL-18 stimulated autoreactively activated NKT cells to secrete IFN-, and this was mediated by Janus kinase-signal transducers and activators of transcription (JAK-STAT)–dependent signaling without induction of calcium flux. This pathway did not require concurrent contact with CD1d+ APCs but was strictly dependent on preceding autoreactive stimulation that induced ERK activation. In contrast, NKT-cell responses to the glycolipid antigen -galactosyl ceramide (-GalCer) were dampened by prior autoreactive activation. These results show that NKT-cell autoreactivity induces restricted cytokine secretion and leads to altered basal activation that potentiates innate responsiveness to costimulatory cytokines while modulating sensitivity to foreign antigens. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

	Copyright © 2008 by American Society of Hematology         Online ISSN: 1528-0020