Bacterial glycolipids and analogs as antigens for CD1d-restricted NKT cells

Wu, Dawei; Xing, Guo‐wen; Poles, Michael A.; Horowitz, Amir; Kinjo, Yuki; Sullivan, Barbara A.; Bodmer-Narkevitch, Vera; Plettenburg, Oliver; Kronenberg, Mitchell; Tsuji, Moriya; Ho, David D.; Wong, Chi‐Huey

doi:10.1073/pnas.0408696102

Cited by 221 publications

(195 citation statements)

References 33 publications

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“…Although Wu et al [25] had used synthetic a-GlcUCer to show that it is a CD1d-restricted antigen for NKT cells, this is in support of our results using natural a-GlcUCer extracted from S. paucimobilis. GSL-4A by itself did not stimulate NKT cell cytokine production any more than vehicle treatment and therefore served as a proper control for the bacterial-derived a-GlcUCer.…”

Section: A-glcucer Is the Nkt Cell Activating Ligandsupporting

confidence: 90%

“…During the preparation of this manuscript, Wu et al [25] reported that glycolipids from a related species (S. wittichii) can activate human and mouse NKT cells. Although Wu et al [25] had used synthetic a-GlcUCer to show that it is a CD1d-restricted antigen for NKT cells, this is in support of our results using natural a-GlcUCer extracted from S. paucimobilis.…”

Section: A-glcucer Is the Nkt Cell Activating Ligandmentioning

confidence: 99%

“…5). Thus, the fact that a-GlcUCer (but not GSL-4A) could be efficiently presented when the cells were fixed leads us to conclude that a-GlcUCer (unlike GSL-4A) does not require extensive intracellular processing before presentation.During the preparation of this manuscript, Wu et al [25] reported that glycolipids from a related species (S. wittichii) can activate human and mouse NKT cells. Although Wu et al [25] had used synthetic a-GlcUCer to show that it is a CD1d-restricted antigen for NKT cells, this is in support of our results using natural a-GlcUCer extracted from S. paucimobilis.…”

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confidence: 99%

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Cell wall glycosphingolipids ofSphingomonas paucimobilisare CD1d-specific ligands for NKT cells

et al. 2005

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The current consensus on characterization of NKT cells is based on their reactivity to the synthetic glycolipid, a-galactosylceramide (a-GalCer) in a CD1d-dependent manner. Because of the limited availability of a-GalCer, there is a constant search for CD1d-presented ligands that activate NKT cells. The a-anomericity of the carbohydrate is considered to be an important requisite for the CD1d-specific activation of NKT cells. The gram-negative, lipopolysaccharide-free bacterium Sphingomonas paucimobilis is known to contain glycosphingolipids (GSL) with a-anomeric sugars attached to the lipid chain. Here, we report that GSL extracted from this bacterium are able to stimulate NKT cells in a CD1d-specific manner. In addition, soluble CD1d-Ig dimers loaded with this lipid extract specifically bind to NKT cells (but not conventional T cells). Further studies on the S. paucimobilis GSL could potentially lead to other natural sources of CD1d-specific ligands useful for NKT cell analyses and aimed at identifying novel therapies for a variety of disease states. IntroductionLipid antigens, including phospholipids and glycosphingolipids (GSL), are presented by CD1d -a subset of the CD1 family of MHC class I-like molecules -to specialized immune effector cells called NKT cells [1]. Located on a different chromosome than the MHC, five different CD1 genes encode CD1 molecules -CD1a, CD1b, CD1c, CD1d and CD1e -in humans, whereas only two homologues of CD1d (CD1d1 and CD1d2) are present in mice [2]. On the basis of the crystal structure of mouse CD1d1 [3], it is predicted that the fatty-acyl chains are buried in the hydrophobic pocket of the molecule with the hydrophilic head-group of the lipid antigen available outside the molecule for its interaction with the NKT cell receptor. Even though the lipidbinding groove of CD1d is widely accommodative of many lipid groups, it is believed that only the sugar structures in a-anomeric orientation are able to stimulate NKT cells [4]. Because of the lack of physiological glycolipids with terminal a-anomeric sugars, it is hypothesized that both altered selfglycolipids during a pathological process and exogenous antigenic glycolipids could be potential ligands presented by CD1d [4]. The presence of GSL in the cell wall of some bacterial strains indicates the possibility of these bacterial GSL being presented by CD1d. Although human CD1a, b and c molecules are known to present mycobacterial antigens to human NKT cells, there is a lack of substantial evidence to show that CD1d has the ability to present these microbial lipids [5]. In a recent study, Fischer et al. [6] were able to show that mycobacterial phosphoinositolmannosides (PIM) could bind to soluble CD1d and activate human and mouse NKT cells. However, only a fraction of NKT cells detected by agalactosylceramide (a-GalCer) could be stained by a CD1d tetramer loaded with mycobacterial PIM [6]. A recent study [7] was able to show the binding of synthetic a-GalNAc containing GSL to cell surface CD1d, but no functional studies were done t...

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Section: A-glcucer Is the Nkt Cell Activating Ligandsupporting

confidence: 90%

Section: A-glcucer Is the Nkt Cell Activating Ligandmentioning

confidence: 99%

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Cell wall glycosphingolipids ofSphingomonas paucimobilisare CD1d-specific ligands for NKT cells

et al. 2005

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“…a-glucuronosylceramide from Sphingomonas sp. [26][27][28][29] and Ehrlichia sp. [28], a-galactosyldiacylglycerol from Borrelia sp.…”

Section: Introductionmentioning

confidence: 99%

“…a-glucuronosylceramide from Sphingomonas sp. [26][27][28][29] and Ehrlichia sp.[28], a-galactosyldiacylglycerol from Borrelia sp.[30], phosphatidylinositol mannoside from Mycobacterium sp.[31] and phosphoethanolamine [32] have recently been identified as ligands for iNKT cells, although all of these activate iNKT cells to a lesser degree than a-GalCer. Although lysosomal glycosphingolipid, isoglobotrihexosylceramide has been reported as a possible endogenous ligand for iNKT cells [28,33], a recent study argues against this possibility [34].…”

mentioning

confidence: 99%

Retracted: α‐GalCer ameliorates listeriosis by accelerating infiltration of Gr‐1⁺ cells into the liver

Emoto

Yoshizawa

et al. 2010

Eur J Immunol

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a-Galactosylceramide (a-GalCer) activates invariant (i)NKT cells, which in turn stimulate immunocompetent cells. Although activation of iNKT cells appears critical for regulation of immune responses, it remains elusive whether protection against intracellular bacteria can be induced by a-GalCer. Here, we show that a-GalCer treatment ameliorates murine listeriosis, and inhibits inflammation following Listeria monocytogenes infection. Liver infiltration of Gr-1 1 cells and c/d T cells was accelerated by a-GalCer treatment. Gr-1 1 cell and c/d T-cell depletion exacerbated listeriosis in a-GalCer-treated mice, and this effect was more pronounced after depletion of Gr-1 1 cells than that of c/d T cells. Although GM-CSF and IL-17 were secreted by NKT cells after a-GalCer treatment, liver infiltration of Gr-1 1 cells was not prevented by neutralizing mAb. In parallel to the numerical increase of CD11b 1 Gr-1 1 cells in the liver following a-GalCer treatment, CD11b À Gr-1 1 cells were numerically reduced in the bone marrow. In addition, respiratory burst in Gr-1 1 cells was enhanced by a-GalCer treatment. Our results indicate that a-GalCer-induced antibacterial immunity is caused, in part, by accelerated infiltration of Gr-1 1 cells and to a lesser degree of c/d T cells into the liver. We also suggest that the infiltration of Gr-1 1 cells is caused by an accelerated supply from the bone marrow.Key words: a-galactosylceramide . L. monocytogenes . NKT cell Supporting Information available online IntroductionListeria monocytogenes is a Gram-positive facultative intracellular bacterial pathogen, which causes disseminated infection in immunocompromised hosts [1]. Experimental murine listeriosis is instrumental in elucidating host defense mechanisms against intracellular bacteria. Cells of the innate immune system play a pivotal role as a first line of defense against L. monocytogenes [2-5] and among these, Gr-1 1 cells are central for the elimination of this pathogen at early stages of infection [6][7][8]. Numerous cytokines such as GM-CSF, IL-3, IL-6, IL-11, and SCF promote granulopoiesis by themselves and/or in concert with G-CSF [9,10]. G-CSF is indispensable for both steady-state and emergency granulopoiesis [11][12][13][14], and IL-17 regulates G-CSF secretion [9,10,[15][16][17][18]. In addition to Gr-1 1 cells, g/d T cells also participate in early protection against 1328L. monocytogenes infection [19][20][21][22]. The vast majority of L. monocytogenes organisms are trapped in the liver immediately after systemic infection [23] and hence, immunocompetent cells that reside in, and/or migrate into, the liver are critical for infection control.NKT cells represent a unique subset of T lymphocytes, which are characterized by the co-expression of NK cell markers such as NKR-P1B/C (NK1.1; CD161) [24]. In the mouse, the majority of NKT cells express an invariant (i) TCR composed of Va14/Ja18 gene segments, i.e. iNKT cells [24]. In contrast to conventional T cells, which recognize peptide antigens presented by polymorphic MHC ...

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Glycolipid Presentation by CD1

Libero

2007

Encyclopedia of Life Sciences

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T cells recognize lipid antigens as complexes associated with CD1 antigen-presenting molecules. The biophysical properties of lipids impose unique mechanisms for lipid delivery, cell internalization, membrane trafficking, processing of large glycolipid antigens and loading of CD1 molecules. T cells specific for lipid antigens participate in the regulation of immune response, protection during infections and pathogenesis of autoimmune diseases.

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Bacterial glycolipids and analogs as antigens for CD1d-restricted NKT cells

Cited by 221 publications

References 33 publications

Cell wall glycosphingolipids ofSphingomonas paucimobilisare CD1d-specific ligands for NKT cells

Cell wall glycosphingolipids ofSphingomonas paucimobilisare CD1d-specific ligands for NKT cells

Retracted: α‐GalCer ameliorates listeriosis by accelerating infiltration of Gr‐1⁺ cells into the liver

Glycolipid Presentation by CD1

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Bacterial glycolipids and analogs as antigens for CD1d-restricted NKT cells

Cited by 221 publications

References 33 publications

Cell wall glycosphingolipids ofSphingomonas paucimobilisare CD1d-specific ligands for NKT cells

Cell wall glycosphingolipids ofSphingomonas paucimobilisare CD1d-specific ligands for NKT cells

Retracted: α‐GalCer ameliorates listeriosis by accelerating infiltration of Gr‐1+ cells into the liver

Glycolipid Presentation by CD1

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Retracted: α‐GalCer ameliorates listeriosis by accelerating infiltration of Gr‐1⁺ cells into the liver