Yalong Zhang

Adaptability of the semi-invariant natural killer T-cell receptor towards structurally diverse CD1d-restricted ligands

The semi‐invariant natural killer (NK) T‐cell receptor (NKTcr) recognises structurally diverse glycolipid antigens presented by the monomorphic CD1d molecule. While the α‐chain of the NKTcr is invariant, the β‐chain is more diverse, but how this diversity enables the NKTcr to recognise diverse antigens, such as an α‐linked monosaccharide (α‐galactosylceramide and α‐galactosyldiacylglycerol) and the β‐linked trisaccharide (isoglobotriaosylceramide), is unclear. We demonstrate here that NKTcrs, which varied in their β‐chain usage, recognised diverse glycolipid antigens with a similar binding mode on CD1d. Nevertheless, the NKTcrs recognised distinct epitopic sites within these antigens, including α‐galactosylceramide, the structurally similar α‐galactosyldiacylglycerol and the very distinct isoglobotriaosylceramide. We also show that the relative roles of the CDR loops within the NKTcr β‐chain varied as a function of the antigen. Thus, while NKTcrs characteristically use a conserved docking mode, the NKTcr β‐chain allows these cells to recognise unique aspects of structurally diverse CD1d‐restricted ligands.

Trapping norovirus by glycosylated hydrogels: a potential oral antiviral drug.

Acute gastroenteritis is a common disease in humans. Each year there are 700 million cases of acute diarrhea, including 2.5–3.2 million deaths of children under the age of five. 2] Recent studies indicate that the majority of acute viral gastroenteritis episodes are caused by noroviruses. Noroviruses cause large-scale outbreaks of acute diarrhea through water and food contamination, resulting in public panic. The outbreaks can also bring unnecessary situations of stress, such as foreign military operations. Its highly contagious nature and high resistance to disinfectants make norovirus and its associated diseases difficult to control. They have therefore been categorized as B agents in the NIH/CDC biodefense program. Norovirus, also called Norwalk-like virus, has been found to recognize human histo-blood group antigens (HBGAs). HBGAs are complex carbohydrates linked to glycoproteins or glycolipids located on the surface of red blood cells and mucosal epithelial cells. They are also present as free antigens in biological fluids such as blood, saliva, intestinal contents, and milk. Huang and co-workers demonstrated that different noroviruses can recognize different HBGAs. The research groups of Lee, Whitesides, and others 11] have demonstrated that the polyvalent form of carbohydrate ligands, either polymeror dendrimer-based, can significantly increase carbohydrate binding to bacterial or viral lectins. Eklind and co-workers prepared Lewis B derivatives co-polymerized with acrylamide to inhibit the growth of Helicobacter pylori. However, there are two limitations in the application of linear polymers or dendrimers as oral antiviral drugs: 1) a large quantity of polymer or dendrimer is required to efficiently bind noroviruses located in the intestinal tract owing to the high solubility of the polymer in aqueous solution and 2) because of polydispersity, the low-molecular-weight fraction of the linear glycosylated polymer, especially species smaller than 200 nm in diameter, may enter the blood vessels and cause severe side effects. To overcome these limitations, glycosylated hydrogels were applied to trap noroviruses. Hydrogels are cross-linked polymers and are insoluble in water, but can swell from several to a few thousand times their original weight by absorbing water. Hydrogels are also stable in acidic or alkaline environments due to their covalent nature. Through these characteristics, hydrogels resemble living tissues in their physical properties, biocompatibility, and nontoxicity. As a result, hydrogels are widely used as drug-delivery systems. Herein we report a new method to trap norovirus in an HBGA-containing hydrogel (Figure 1). Glycosylated hydrogels have the potential for use as oral prophylactic antiviral drugs by trapping norovirus inside their mesh through a “caged polyvalent effect”. The norovirus entrapped in the hydrogels could then be excreted from the body through the normal GI tract.

The Roles of 3 ' and 4 ' Hydroxy Groups in alpha-Galactosylceramide Stimulation of Invariant Natural Killer T Cells

The marine-derived α-galactosylceramide is an exogenous ligand for natural killer T cells and leads to the secretion of both T help 1 (Th1) and Th2 cytokines. The relationship between the sugar moiety structure and invariant natural killer T (iNKT) cell stimulation ability has not been fully understood. With the series α-galactosylceramide analogues varied on C3′ and C4′ position, subjected to a murine system, we discovered that the 3′ hydroxyl is very crucial in maintaining the molecule’s immunogenicity. Any modification on this position will lead to the losing of activity. We also found that the C4′ position is not so sensitive and can tolerate some small modifications on it. Moreover, the C4′ substituted analogues induced biased Th2 cytokines release was observed.

Erratum: Adaptability of the semi-invariant natural killer T-cell receptor towards structurally diverse CD1d-restricted ligands (The EMBO Journal (2009) 28 (3579-3590) DOI: 10.1038/emboj.2009.286

Department of Microbiology and Immunology, Vanderbilt University, School of Medicine, Nashville, TN, USA, Department of Chemistry and Biochemistry, Ohio State University, Columbus, OH, USA, National Jewish Centre for Allergy and Immunology Research, Denver, CO, USA, Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA, Department of Chemistry, University of Connecticut, Storrs, CT, USA, Department of Microbiology and Immunology, University of Melbourne, Melbourne, Victoria, Australia, Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria, Australia, Fox Chase Cancer Centre, Philadelphia, PA, USA and Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA