The Vα14 NKT Cell TCR Exhibits High-Affinity Binding to a Glycolipid/CD1d Complex

Sidobre, Stéphane; Naidenko, Olga V.; Sim, Bee-Cheng; Gascoigne, Nicholas R. J.; García, K. Christopher; Kronenberg, Mitchell

doi:10.4049/jimmunol.169.3.1340

Cited by 117 publications

(102 citation statements)

References 59 publications

(91 reference statements)

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“…Even though only *50% of a-GalCer-specific invariant NKT cells were detected by using a-GlcUCer, this proportion is significantly higher than that reported using PIM [6], and could indicate a subpopulation of NKT cells [31]. Unlike a-GalCer-loaded tetramers [30,32,33], the lipid-loaded CD1d-Ig dimers exhibit a Vbdependent staining of invariant NKT cells [31]. Therefore, the subset of NKT cells detected by a-GlcUCerloaded dimers have TCR with a-or b-chains that are not affected by the negatively charged carboxylic acid group Highlights 1697 of a-GlcUCer that distinguishes it from a-GalCer.…”

Section: A-glcucer Is the Nkt Cell Activating Ligandmentioning

confidence: 72%

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 Ligandmentioning

confidence: 72%

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

et al. 2005

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“…Moreover, the reason for the apparent discrepancy of Con A and anti-CD3 mAb vs ␣-GalCer on NKT cell apoptosis is unknown. It is possible that the ability of Con A and anti-CD3 mAb to both directly activate the TCR (48) to mediate their effects, whereas ␣-GalCer is known to bind to CD1d before activation of the TCR (32,36,39) may underlie this discrepancy. Regardless, our data emphasize the fact that NKT cells are more prone to AICD when directly activated through the TCR.…”

Section: Discussionmentioning

confidence: 94%

“…NKT cells have the unusual property of recognizing glycolipid Ags in conjunction with the MHC class I-like molecule, CD1d (32)(33)(34)(35), and are abundant in the liver, thymus, and to a lesser extent in the spleen and bone marrow (31, 36 -39). Previous studies have demonstrated that CD1d gene-deficient and V␣14 gene-deficient mice, which express very few NKT cells, are resistant to Con A-induced hepatitis (11,24,40).…”

Section: Discussionmentioning

confidence: 99%

“…NKT cells are a unique T cell lineage that are defined as cells that coexpress the NK cell marker (usually NK1.1) and a highly restricted TCR specific for glycolipid Ag (31)(32)(33). NKT cells have the unusual property of recognizing glycolipid Ags in conjunction with the MHC class I-like molecule, CD1d (32)(33)(34)(35), and are abundant in the liver, thymus, and to a lesser extent in the spleen and bone marrow (31, 36 -39).…”

Section: Discussionmentioning

confidence: 99%

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Lack of Chemokine Receptor CCR5 Promotes Murine Fulminant Liver Failure by Preventing the Apoptosis of Activated CD1d-Restricted NKT Cells

Ajuebor¹,

Aspinall²,

Zhou³

et al. 2005

The Journal of Immunology

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102

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Fulminant liver failure (FLF) consists of a cascade of events beginning with a presumed uncontrolled systemic activation of the immune system. The etiology of FLF remains undefined. In this study, we demonstrate that CCR5 deficiency promotes the development of acute FLF in mice following Con A administration by preventing activated hepatic CD1d-restricted NKT cells (but not conventional T cells) from dying from activation-induced apoptosis. The resistance of CCR5-deficient NKT cells from activation-induced apoptosis following Con A administration is not due to a defective Fas-driven death pathway. Moreover, FLF in CCR5-deficient mice also correlated with hepatic CCR5-deficient NKT cells, producing more IL-4, but not IFN-γ, relative to wild-type NKT cells. Furthermore, FLF in these mice was abolished by IL-4 mAb or NK1.1 mAb treatment. We propose that CCR5 deficiency may predispose individuals to the development of FLF by preventing hepatic NKT cell apoptosis and by regulating NKT cell function, establishing a novel role for CCR5 in the development of this catastrophic liver disease that is independent of leukocyte recruitment.

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“…Although the natural antigen(s) that stimulate the majority of V␣14i NKT cells have not been unequivocally identified, V␣14i NKT cells are strongly reactive to a synthetic version of a marine sponge-derived glycolipid: ␣-galactosyl ceramide (␣-GalCer) (14). We and others have shown previously that the TCR of V␣14i NKT cells exhibits a high-affinity binding to the ␣-GalCer͞CD1d complex and a long half-life (t 1/2 ) (15)(16)(17)(18). ␣-GalCer is a very potent antigen, however, and it was not certain if those properties are linked to the peculiar nature of this antigen, or if they reflect the intrinsic requirements for the activation of V␣14i NKT cells.…”

Section: Ost T Lymphocytes Recognize Antigenic Peptides Presentedmentioning

confidence: 99%

The T cell antigen receptor expressed by Vα14iNKT cells has a unique mode of glycosphingolipid antigen recognition

Sidobre

Hammond

Bénazet-Sidobre

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Natural killer (NK) T cells with an invariant V␣14 rearrangement (V␣14i) are the largest population of lipid antigen-specific T lymphocytes identified in animals. They react to the glycolipid ␣-galactosyl ceramide (␣-GalCer) presented by CD1d, and they may have important regulatory functions. It was previously shown that the V␣14i T cell antigen receptor (TCR) has a high affinity for the ␣-GalCer͞CD1d complex, driven by a long half-life (t 1/2 ). Although this result could have reflected the unique attributes of ␣-GalCer, using several related glycolipid compounds, we show here that the threshold for full activation of V␣14i NKT cells by these glycosphingolipids requires a relatively high-affinity TCR interaction with a long t 1/2. Furthermore, our data are consistent with the view that the mechanism of recognition of these compounds presented by CD1d to the V␣14i NKT cell TCR is likely to fit a lock-and-key model. Overall, these findings emphasize the distinct properties of glycosphingolipid antigen recognition by V␣14i NKT cells.

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The Vα14 NKT Cell TCR Exhibits High-Affinity Binding to a Glycolipid/CD1d Complex

Cited by 117 publications

References 59 publications

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

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

Lack of Chemokine Receptor CCR5 Promotes Murine Fulminant Liver Failure by Preventing the Apoptosis of Activated CD1d-Restricted NKT Cells

The T cell antigen receptor expressed by Vα14iNKT cells has a unique mode of glycosphingolipid antigen recognition

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