title: Insights into spatial configuration of a galactosylated epitope required to trigger arthritogenic T-cell receptors specific for the sugar moiety.
abstract: The immunodominant epitope of bovine type II collagen (CII256-270) in Aq mice carries a hydroxylysine-264 linked galactose (Gal-Hyl264), the recognition of which is central to the development of collagen-induced arthritis. This study explores the molecular interactions involved in the engagement of T-cell receptors (TCRs) with such epitopes. Responses of three anti-CII T-cell hybridomas and clone A9.2 (all sharing close TCR sequences) to a panel of CII256-270 analogues incorporating Gal-Hyl264 with a modified side chain were determined. Recognition of naturally occurring CII256-270 peptides by either group of T cells depended strictly upon the presence of the carbohydrate and, more precisely, its intact HO-4 group. Modifications of primary amino group on the hydroxylysine side chain eliminated T-cell reactivity, notwithstanding the presence of the galactosyl moiety. Moderate stereochemical changes, such as altered sugar orientation and methylation at the galactose anchor position, were still permissive. Conversely, robust transformations affecting the relative positions of the key elements were detrimental to TCR recognition. To conclude, these data provide strong new experimental evidence that integrity of both galactose HO-4 and hydroxylysine side chain primary amino groups are mandatory for activation of anti-Gal-Hyl264 TCRs. They also indicate that there is a certain degree of TCR plasticity in peptide-TCR interactions.
authors.affiliation: Institut Cochin, Université Paris Descartes CNRS (UMR 8104), 27 rue du Fbg Saint Jacques, Paris, F-75014, France. glatigny@cochin.inserm.fr
authors.forename: Simon
authors.initials: S
authors.lastname: Glatigny
authors.forename: Marie-Agnès
authors.initials: MA
authors.lastname: Blaton
authors.forename: Julien
authors.initials: J
authors.lastname: Marin
authors.forename: Sylvie
authors.initials: S
authors.lastname: Mistou
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Briand
authors.forename: Gilles
authors.initials: G
authors.lastname: Guichard
authors.forename: Catherine
authors.initials: C
authors.lastname: Fournier
authors.forename: Gilles
authors.initials: G
authors.lastname: Chiocchia
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism*; D001665:Binding Sites / Q000502:physiology; D002417:Cattle; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000378:metabolism*; D005690:Galactose / Q000737:chemistry* / Q000378:metabolism*; D051379:Mice; D008811:Mice, Inbred DBA; D008968:Molecular Conformation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*
chemical_list: D018984:Epitopes, T-Lymphocyte; D011948:Receptors, Antigen, T-Cell; D005690:Galactose