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      Invariant natural killer T cells recognize lipid self-antigen induced by microbial danger signals

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          Abstract

          Invariant natural killer T cells (iNKT cells) play a prominent role during infection and other inflammatory processes, and these cells can be activated through their T cell receptors by microbial lipid antigens. However, increasing evidence shows that they are also activated in situations where no foreign lipid antigens are present, suggesting a role for lipid self-antigen. We now demonstrate that an abundant endogenous lipid, β-D-glucopyranosylceramide (β-GlcCer), is a potent iNKT cell self-antigen in mouse and human, and that its activity depends on N-acyl chain composition. Furthermore, β-GlcCer accumulates during infection and in response to Toll-like receptor agonists, contributing to iNKT cell activation. Thus, we propose that recognition of β-GlcCer by the invariant TCR translates innate danger signals into iNKT cell activation.

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          Most cited references 44

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          CD1d-restricted and TCR-mediated activation of valpha14 NKT cells by glycosylceramides.

           J Cui,  H Koseki,  I Toura (1997)
          Natural killer T (NKT) lymphocytes express an invariant T cell antigen receptor (TCR) encoded by the Valpha14 and Jalpha281 gene segments. A glycosylceramide-containing alpha-anomeric sugar with a longer fatty acyl chain (C26) and sphingosine base (C18) was identified as a ligand for this TCR. Glycosylceramide-mediated proliferative responses of Valpha14 NKT cells were abrogated by treatment with chloroquine-concanamycin A or by monoclonal antibodies against CD1d/Vbeta8, CD40/CD40L, or B7/CTLA-4/CD28, but not by interference with the function of a transporter-associated protein. Thus, this lymphocyte shares distinct recognition systems with either T or NK cells.
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            CD1: antigen presentation and T cell function.

            This review summarizes the major features of CD1 genes and proteins, the patterns of intracellular trafficking of CD1 molecules, and how they sample different intracellular compartments for self- and foreign lipids. We describe how lipid antigens bind to CD1 molecules with their alkyl chains buried in hydrophobic pockets and expose their polar lipid headgroup whose fine structure is recognized by the TCR of CD1-restricted T cells. CD1-restricted T cells carry out effector, helper, and adjuvant-like functions and interact with other cell types including macrophages, dendritic cells, NK cells, T cells, and B cells, thereby contributing to both innate and adaptive immune responses. Insights gained from mice and humans now delineate the extensive range of diseases in which CD1-restricted T cells play important roles and reveal differences in the role of CD1a, CD1b, and CD1c in contrast to CD1d. Invariant TCR alpha chains, self-lipid reactivity, and rapid effector responses empower a subset of CD1d-restricted T cells (NKT cells) to have unique effector functions without counterpart among MHC-restricted T cells. This review describes the function of CD1-restricted T cells in antimicrobial responses, antitumor immunity, and in regulating the balance between tolerance and autoimmunity.
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              Unbiased reconstruction of a mammalian transcriptional network mediating pathogen responses.

              Models of mammalian regulatory networks controlling gene expression have been inferred from genomic data but have largely not been validated. We present an unbiased strategy to systematically perturb candidate regulators and monitor cellular transcriptional responses. We applied this approach to derive regulatory networks that control the transcriptional response of mouse primary dendritic cells to pathogens. Our approach revealed the regulatory functions of 125 transcription factors, chromatin modifiers, and RNA binding proteins, which enabled the construction of a network model consisting of 24 core regulators and 76 fine-tuners that help to explain how pathogen-sensing pathways achieve specificity. This study establishes a broadly applicable, comprehensive, and unbiased approach to reveal the wiring and functions of a regulatory network controlling a major transcriptional response in primary mammalian cells.
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                Author and article information

                Journal
                100941354
                21750
                Nat Immunol
                Nat. Immunol.
                Nature Immunology
                1529-2908
                1529-2916
                14 October 2011
                30 October 2011
                01 June 2012
                : 12
                : 12
                : 1202-1211
                Affiliations
                [1 ]Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
                [2 ]Academic Unit of Clinical & Experimental Sciences, University of Southampton, Faculty of Medicine, Sir Henry Wellcome and “Hope” Laboratories, United Kingdom
                [3 ]Division of Endocrinology, Metabolism and Lipid Research, Washington University, St. Louis, MO 63110, USA
                [4 ]School of Biosciences, University of Birmingham, Birmingham B15 2TT, UK
                Author notes
                Corresponding author: Michael B. Brenner, Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women’s Hospital, Smith Building, Room 552, One Jimmy Fund Way, Boston, MA 02115, Tel: 617-525-1000, Fax: 617-525-1001, mbrenner@ 123456rics.bwh.harvard.edu
                [5]

                Both authors contributed equally to this work.

                Article
                nihpa326673
                10.1038/ni.2143
                3242449
                22037601
                ea320e26-6767-43e2-95dd-d0868f5afb17
                Funding
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: K08 AI077795-05 || AI
                Categories
                Article

                Immunology

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