Effects of Lipid Chain Lengths in α-Galactosylceramides on Cytokine Release by Natural Killer T Cells

Goff, Randal D.; Gao, Ying; Mattner, Jochen; Zhou, Dapeng; Yin, Ning; Cantu, Carlos; Teyton, Luc; Bendelac, and Albert; Savage, Paul B.

doi:10.1021/ja045385q

Cited by 197 publications

(171 citation statements)

References 19 publications

Supporting

Mentioning

166

Contrasting

Order By: Relevance

“…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). Based on these findings, we conclude that the combined differences of the shortened acyl chain and the absence of the sphingosine 4-OH have a synergistic effect that is greater than the sum of the individual differences.…”

Section: Resultsmentioning

confidence: 93%

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.

132

128

View full text Add to dashboard Cite

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 ...

show abstract

Section: Resultsmentioning

confidence: 93%

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.

132

128

View full text Add to dashboard Cite

show abstract

“…30 In consideration of the intrinsic instability of O-glycosides in vivo, both C-bridged glycoside (α-C-GalCer) 31−33 and S-bridged glycoside (α-S-GalCer), 34−36 with the replacement of the anomeric oxygen by methylene or sulfur atom, respectively, were prepared to examine their biological activities. Comparing to the O-glycoside KRN7000, α-C-GalCer showed a stronger Th1 response in vivo, whereas the analogue α-S-GalCer did not activate the murine iNKT cells both in vitro and in vivo, but stimulated human iNKT cells in vitro.…”

Section: −27mentioning

confidence: 99%

“…23−27 For example, KRN7000 analogue with a longer acyl tail (2, Figure 1) exhibited a greater ability for activation of B cells and induced IL-2 from mouse NKT cells, and IL-4 and IFN-γ from human Vα24i NKT cells in vitro, 28,29 while the analogue with a relative shorter chain (3, Figure 1) influenced cytokine release toward Th2 bias with an immunomodulatory response. 30 In consideration of the intrinsic instability of O-glycosides in vivo, both C-bridged glycoside (α-C-GalCer) 31−33 and S-bridged glycoside (α-S-GalCer), 34−36 with the replacement of the anomeric oxygen by methylene or sulfur atom, respectively, were prepared to examine their biological activities. Comparing to the O-glycoside KRN7000, α-C-GalCer showed a stronger Th1 response in vivo, whereas the analogue α-S-GalCer did not activate the murine iNKT cells both in vitro and in vivo, but stimulated human iNKT cells in vitro.…”

mentioning

confidence: 99%

Synthesis and Biological Activities of 5-Thio-α-GalCers

Wang

Zhou

et al. 2015

ACS Med. Chem. Lett.

View full text Add to dashboard Cite

NKT cells, a unique subset of T cells that recognizes glycolipid antigens presented by CD1d molecules, are believed to produce key cytokines of both Th1 and Th2 T cells and are thus involved in the control of several types of immune response. As an active glycolipid antigen having α-galactosyl ceramide core structure, KRN7000 showed promising immunostimulation activity and was selected as an anticancer drug candidate for further clinical application. In this report, three new KRN7000 structural analogues were designed and synthesized, in which the ring oxygen of the galactopyranose residue is replaced by a sulfur atom along with the variation on the lipid chain. Their abilities for stimulating mouse NKT cells to produce IFN-γ and IL-4 were evaluated both in vivo and in vitro. KEYWORDS: KRN7000, 5-thio-α-GalCer, iNKT cells, antitumor activity I nvariant natural killer T (iNKT) cells are a specialized subset of T cells that play an important role in tumor immunity and preventing autoimmunity.1−4 The anti-infective activity of iNKT cells can be triggered by various viruses, bacteria, and parasites. 5,6 When stimulated by glycolipid antigens such as marine natural product agelasphin-9b, 7 the iNKT cells could rapidly release T helper 1 (Th1) cytokines (e.g., IFN-γ, TNF-α, IF-2) and Th2 cytokines (e.g., IL-4, IL-10).8,9 Th1-biased cytokines are believed to be concerned with the antitumor, antibacterial, and antiviral activities, whereas the release of Th2-biased cytokines may relieve some autoimmune diseases.10−12 KRN7000 (1), 13 a synthetic α-GalCer (1, Figure 1) derived from the structural modification on the ceramide part of agelasphin-9b, presented convincing effects on the treatment of liver tumors, 14,15 metastatic cancers, 16,17 parasitic infections, 11,18 and autoimmune diseases. 19,20 The action mechanism of KRN7000 has been suggested in approximately three sequential steps. First, KRN7000 is combined with the CD1d protein to form a glycolipid−protein complex. Second, the KRN7000/CD1d complex is recognized by the T cell receptor (TCR) on the surface of NKT cells to form a three-molecule complex. Lastly, it stimulates NKT cells to release Th1 and Th2 cytokines rapidly. 21 Because of the mutual repulsion of Th1 and Th2 cytokines, the simultaneous high level production of both cytokines weaken the therapeutic effectiveness of KRN7000. 22Therefore, some KRN7000 derivatives modifying on either sugar or ceramide moieties were synthesized and expected to selectively control the release of Th1 and Th2 cytokines. 23−27For example, KRN7000 analogue with a longer acyl tail (2, Figure 1) exhibited a greater ability for activation of B cells and induced IL-2 from mouse NKT cells, and IL-4 and IFN-γ from human Vα24i NKT cells in vitro, 28,29 while the analogue with a relative shorter chain (3, Figure 1) influenced cytokine release toward Th2 bias with an immunomodulatory response. 30 In consideration of the intrinsic instability of O-glycosides in vivo, both C-bridged glycoside (α-C-GalCer) 31−33 and S-bridged ...

show abstract

“…Savage and coworkers showed that truncation of the fatty acyl or the phytosphingosine chains has shown to bias cytokine secretion toward a Th2 response. 45 Similarly, OCH selectively induces Th2 cytokines from NKT cells and suppressed autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE) and diabetes in NOD mice. 46 Also, introduction of unsaturation into the fatty acyl chain of α-GalCer, C20:1 cis/trans and C20:2 analogs seem to bias toward a Th2 response.…”

Section: Modification Of Lipid Chainsmentioning

confidence: 99%

Glycolipids as immunostimulating agents

Fujio

Wong

2008

Bioorganic & Medicinal Chemistry

110

View full text Add to dashboard Cite

The processing and presentation of lipid antigens by antigen presenting cells (APC) is important for defense against infection, tumor immunosurveillance, and autoimmunity. CD1, a family of cell surface glycoproteins, is responsible for the binding and presentation of lipid antigens to receptors expressed on the surface of T lymphocytes. Among the several (glyco)lipids identified to cause Tcell stimulation in complex with CD1, α-galactosyl ceramide (α-Galcer), is one of the most well studied. A combination of structure-activity relationship (SAR), crystallographic studies, and discovery of new "natural" antigens has led to greater understanding of the structural requirements for optimal natural killer T-cell activation.

show abstract

Effects of Lipid Chain Lengths in α-Galactosylceramides on Cytokine Release by Natural Killer T Cells

Cited by 197 publications

References 19 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

Synthesis and Biological Activities of 5-Thio-α-GalCers

Glycolipids as immunostimulating agents

Contact Info

Product

Resources

About