title: Synthesis and structure-activity relationship study of isoglobotrihexosylceramide analogues.
abstract: Invariant natural killer T (iNKT) cells are innate T lymphocytes that express T cell receptors binding to exogenous and endogenous glycosphingolpid antigens presented by a nonpolymorphic, non-MHC antigen presenting molecule, CD1d. The endogenous glycosphingolipid metabolite, isoglobotrihexosylceramide (iGb3), is the first known natural ligand for both human and mouse iNKT cells, whose activity has been confirmed in a variety of iNKT cell clones generated by different investigators, representing the majority of the iNKT cell population. The signaling pathway mediated by T cell receptor is largely influenced by the structural variation of glycosphingolpid antigens, leading to multiple and varied biological functions of iNKT cells. In order to investigate the structural requirements behind iGb3 triggered iNKT cell activation, the structure-activity relationship (SAR) of iGb3 needs to be characterized. In this study, iGb3 analogues containing 2' '', 3' '', 4' '' and 6' '' deoxy terminal galactose were synthesized for probing the SAR between iGb3 and TCR. The biological assays on the synthetic iGb3 analogues were performed with use of the murine iNKT cell hybridoma DN32.D3. The results showed that the 2' '' and 3' '' hydroxyl groups of terminal galactose play more important roles for the recognition of iGb3 by TCR; while 4' '' and 6' '' hydroxyl groups were not as crucial for this recognition. These studies might help to understand the general structural requirements for natural endogenous ligands recognized by iNKT cells.
authors.affiliation: Department of Chemistry, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Wenlan
authors.initials: W
authors.lastname: Chen
authors.forename: Chengfeng
authors.initials: C
authors.lastname: Xia
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wang
authors.forename: Prakash
authors.initials: P
authors.lastname: Thapa
authors.forename: Yusen
authors.initials: Y
authors.lastname: Li
authors.forename: Arindam
authors.initials: A
authors.lastname: Talukdar
authors.forename: Janos
authors.initials: J
authors.lastname: Nadas
authors.forename: Wenpeng
authors.initials: W
authors.lastname: Zhang
authors.forename: Dapeng
authors.initials: D
authors.lastname: Zhou
authors.forename: Peng George
authors.initials: PG
authors.lastname: Wang
mesh_terms: D000818:Animals; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D005915:Globosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006825:Hybridomas / Q000187:drug effects* / Q000276:immunology; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D011948:Receptors, Antigen, T-Cell / Q000187:drug effects* / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013329:Structure-Activity Relationship; D014281:Trihexosylceramides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D005915:Globosides; D008024:Ligands; D011948:Receptors, Antigen, T-Cell; D014281:Trihexosylceramides; C514781:isoglobotrihexosylceramide