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Polar functional group-containing glycolipid CD1d ligands modulate cytokine-biasing responses and prevent experimental colitis.

ABSTRACT: The MHC class I-like molecule CD1d is a nonpolymorphic antigen-presenting glycoprotein, and its ligands include glycolipids, such as ?-GalCer. The complexes between CD1d and ligands activate natural killer T cells by T cell receptor recognition, leading to the secretion of various cytokines (IFN-?, IL-4, IL-17A, etc.). Herein, we report structure-activity relationship studies of ?-GalCer derivatives containing various functional groups in their lipid acyl chains. Several derivatives have been identified as potent CD1d ligands displaying higher cytokine induction levels and/or unique cytokine polarization. The studies also indicated that flexibility of the lipid moiety can affect the binding affinity, the total cytokine production level and/or cytokine biasing. Based on our immunological evaluation and investigation of physicochemical properties, we chose bisamide- and Bz amide-containing derivatives 2 and 3, and evaluated their in vivo efficacy in a DSS-induced model of ulcerative colitis. The derivative 3 that exhibits Th2- and Th17-biasing responses, demonstrated significant protective effects against intestinal inflammation in the DSS-induced model, after a single intraperitoneal injection.

SUBMITTER: Inuki S

PROVIDER: S-EPMC7519074 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Polar functional group-containing glycolipid CD1d ligands modulate cytokine-biasing responses and prevent experimental colitis.

Inuki Shinsuke S Hirata Natsumi N Kashiwabara Emi E Kishi Junichiro J Aiba Toshihiko T Teratani Toshiaki T Nakamura Wataru W Kojima Yoshimi Y Maruyama Toru T Kanai Takanori T Fujimoto Yukari Y

Scientific reports 20200925 1

The MHC class I-like molecule CD1d is a nonpolymorphic antigen-presenting glycoprotein, and its ligands include glycolipids, such as α-GalCer. The complexes between CD1d and ligands activate natural killer T cells by T cell receptor recognition, leading to the secretion of various cytokines (IFN-γ, IL-4, IL-17A, etc.). Herein, we report structure-activity relationship studies of α-GalCer derivatives containing various functional groups in their lipid acyl chains. Several derivatives have been id ...[more]

PMID: 32978421

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Project description:Invariant natural killer T cells (iNKT cells) are restricted by CD1d molecules and activated upon CD1d-mediated presentation of glycolipids to T cell receptors (TCRs) located on the surface of the cell. Because the cytokine response profile is governed by the structure of the glycolipid, we sought a method for labeling various glycolipids to study their in vivo behavior. The prototypical CD1d agonist, ?-galactosyl ceramide (?-GalCer) 1, instigates a powerful immune response and the generation of a wide range of cytokines when it is presented to iNKT cell TCRs by CD1d molecules. Analysis of crystal structures of the TCR-?-GalCer-CD1d ternary complex identified the ?-methylene unit in the fatty acid side chain, and more specifically the pro-S hydrogen at this position, as a site for incorporating a label. We postulated that modifying the glycolipid in this way would exert a minimal impact on the TCR-glycolipid-CD1d ternary complex, allowing the labeled molecule to function as a good mimic for the CD1d agonist under investigation. To test this hypothesis, the synthesis of a biotinylated version of the CD1d agonist threitol ceramide (ThrCer) was targeted. Both diastereoisomers, epimeric at the label tethering site, were prepared, and functional experiments confirmed the importance of substituting the pro-S, and not the pro-R, hydrogen with the label for optimal activity. Significantly, functional experiments revealed that biotinylated ThrCer (S)-10 displayed behavior comparable to that of ThrCer 5 itself and also confirmed that the biotin residue is available for streptavidin and antibiotin antibody recognition. A second CD1d agonist, namely ?-GalCer C20:2 4, was modified in a similar way, this time with a fluorescent label. The labeled ?-GalCer C20:2 analogue (11) again displayed functional behavior comparable to that of its unlabeled substrate, supporting the notion that the ?-methylene unit in the fatty acid amide chain should be a suitable site for attaching a label to a range of CD1d agonists. The flexibility of the synthetic strategy, and late-stage incorporation of the label, opens up the possibility of using this labeling approach to study the in vivo behavior of a wide range of CD1d agonists.

Dataset Information

Polar functional group-containing glycolipid CD1d ligands modulate cytokine-biasing responses and prevent experimental colitis.

Publications

Polar functional group-containing glycolipid CD1d ligands modulate cytokine-biasing responses and prevent experimental colitis.

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