The T cell antigen receptor expressed by Vα14<i>i</i>NKT cells has a unique mode of glycosphingolipid antigen recognition

Sidobre, Stéphane; Hammond, Kirsten J. L.; Bénazet-Sidobre, Lise; Maltsev, Sergei D.; Richardson, Stewart K.; Ndonye, Rachel M.; Howell, Amy R.; Sakai, Teruyuki; Besra, Gurdyal S.; Porcelli, Steven A.; Kronenberg, Mitchell

doi:10.1073/pnas.0404632101

Cited by 87 publications

(79 citation statements)

References 40 publications

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“…However, the importance of these two positions for TCR contact is strongly suggested by their effects on antigenic potency. For example, ␣-glucosylceramide, which differs from ␣-GalCer only with regard to the orientation of the 4Ј-OH is a less potent antigen with a 10-fold reduced affinity for the TCR when bound to CD1d (28). Similarly, the 6Ј-COOH reduces the antigenic potency and TCR avidity compared with galactose, as detailed above.…”

Section: Resultsmentioning

confidence: 96%

“…The combined data indicate that modifications to the ceramide backbone in the bacterial antigen have a substantial influence on antigenic potency and overall avidity of the trimolecular interaction of TCR, glycolipid, and CD1d. Previously, we showed that absence of the 4-OH alone had a relatively small influence on antigenic potency and a Ͻ5-fold effect on equilibrium binding of a soluble TCR or binding of CD1d tetramers loaded with this variant glycolipid to live cells (28). The shorter C 8 acyl chain of PBS-25 and a C 14 analog of ␣-GalCer also did not cause a great decrease in antigenic potency (29,30).…”

Section: Resultsmentioning

confidence: 99%

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Design of natural killer T cell activators: Structure and function of a microbial glycosphingolipid bound to mouse CD1d

Wu¹,

Zajonc

Fujio³

et al. 2006

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

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132

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Natural killer T (NKT) cells provide an innate-type immune response upon T cell receptor interaction withCD1d-presented antigens. We demonstrate through equilibrium tetramer binding and antigen presentation assays with V␣14i-positive NKT cell hybridomas that the Sphingomonas glycolipid ␣-galacturonosyl ceramide (GalA-GSL) is a NKT cell agonist that is significantly weaker than ␣-galactosylceramide (␣-GalCer), the most potent known NKT agonist. For GalA-GSL, a shorter fatty acyl chain, an absence of the 4-OH on the sphingosine tail and a 6 -COOH group on the galactose moiety account for its observed antigenic potency. We further determined the crystal structure of mCD1d in complex with GalA-GSL at 1.8-Å resolution. The overall binding mode of GalA-GSL to mCD1d is similar to that of the short-chain ␣-GalCer ligand PBS-25, but its sphinganine chain is more deeply inserted into the F pocket due to alternate hydrogen-bonding interactions between the sphinganine 3-OH with Asp-80. Subsequently, a slight lateral shift (>1 Å) of the galacturonosyl head group is noted at the CD1 surface compared with the galactose of ␣-GalCer. Because the relatively short C 14 fatty acid of GalA-GSL does not fully occupy the A pocket, a spacer lipid is found that stabilizes this pocket. The lipid spacer was identified by GC͞MS as a mixture of saturated and monounsaturated palmitic acid (C 16). Comparison of available crystal structures of ␣-anomeric glycosphingolipids now sheds light on the structural basis of their differential antigenic potency and has led to the design and synthesis of NKT cell agonists with enhanced cell-based stimulatory activities compared with ␣-GalCer.adjuvant ͉ glycolipid T he CD1 family of antigen-presenting glycoproteins mediates T cell responses through the presentation of self and foreign lipids, glycolipids, lipopeptides, or amphipathic small molecules to T cell receptors (TCR) (1-10). In humans, the various CD1 isoforms are categorized into group I (CD1a, CD1b, CD1c, and CD1e) and group II (CD1d) based on sequence similarity (11). Through the binding and presentation of endogenous and exogenous lipid antigens to TCRs, the CD1 pathway is reminiscent of peptide presentation by MHC class I and class II molecules.The group II isotype, CD1d, presents antigens to a unique population of T lymphocytes termed natural killer T (NKT) cells (4), which express an invariant V␣14i TCR in mice or V␣24i TCR in humans, in addition to NK 1.1 and other receptors typical of NK cells (12). These cells are sometimes called V␣14i or V␣24i NKT cells to distinguish them from other T lymphocytes that can express NK1.1. The first defined and most potent V␣14i NKT cell agonist, ␣-galactosylceramide (␣-GalCer), was originally isolated from a marine sponge and subsequently optimized by medicinal chemistry (13). When bound to CD1d, ␣-GalCer strongly activates V␣14i NKT cells, causing a rapid release of T helper type 1 and 2 cytokines. Although ␣-GalCer has been of great value and use in exploration of NKT cell biology, its unusual origin ...

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Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Design of natural killer T cell activators: Structure and function of a microbial glycosphingolipid bound to mouse CD1d

Wu¹,

Zajonc

Fujio³

et al. 2006

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

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132

128

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“…CD1d-reactive T cell hybridomas with an invariant V␣14i T cell antigen receptor ␣ chain have been described (27). T cell hybridomas were stimulated with the indicated glycolipids that were added either to plates coated with soluble CD1d, or with CD1d-transfected A20 B lymphoma cells, according to published protocols (28).…”

Section: Hybridoma Assaymentioning

confidence: 99%

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

Xing

Poles

et al. 2005

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

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The CD1 family of proteins binds self and foreign glycolipids for presentation to CD1-restricted T cells. To identify previously uncharacterized active CD1 ligands, especially those of microbial origin, numerous glycolipids were synthesized and tested for their ability to stimulate mouse and human natural killer T (NKT) cells. They included analogs of the well known NKT cell agonist ␣-galactosyl ceramide (␣-GalCer), bacterial glycolipids, and variations of the self-glycolipid, sulfatide. Bacterial glycolipids, ␣-galacturonosyl-ceramides from Sphingomonas wittichii, although structurally similar to ␣-GalCer, have significant differences in the sugar head group as well as the ceramide portion. The Sphingomonas glycosphingolipids (GSLs) and sulfatide variants were shown to activate human NKT cells as measured by IL-4 and IFN-␥ secretion. Moreover, CD1d-dimer staining revealed human NKT cell reactivity toward these GSLs and to the sulfatides in a fashion comparable with ␣-GalCer. Because ␣-GalCer is a marine-sponge-derived ligand, our study here shows that bacterium-derived antigens are also able to stimulate mouse and human NKT cells.

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“…The sugar linked to the sphingoid base plays a prom-inent role in the molecular determinant recognized by the iNKT cell TCR, with a galactose, in most cases, being the most potent moiety (Fig. 1C) (18). Although ␣-linked sugars (Fig.…”

Section: Presentation Of Gsls By Cd1dmentioning

confidence: 99%

The Alpha and Omega of Galactosylceramides in T Cell Immune Function

Birkholz

Howell

Kronenberg

2015

Journal of Biological Chemistry

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Glycosphingolipids are a subgroup of glycolipids that contain an amino alcohol sphingoid base linked to sugars. They are found in the membranes of cells ranging from bacteria to vertebrates. This group of lipids is known to stimulate the immune system through activation of a type of white blood cell known as natural killer T cell (NKT cell). Here we summarize the extensive research that has been done to identify the structures of natural glycolipids that stimulate NKT cells and to determine how these antigens are recognized. We also review studies designed to understand how glycolipid variants, both natural and synthetic, can alter the responses of NKT cells, leading to dramatic changes in the global immune response.

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

Cited by 87 publications

References 40 publications

Design of natural killer T cell activators: Structure and function of a microbial glycosphingolipid bound to mouse CD1d

Design of natural killer T cell activators: Structure and function of a microbial glycosphingolipid bound to mouse CD1d

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

The Alpha and Omega of Galactosylceramides in T Cell Immune Function

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