Side-chain and backbone amide bond requirements for glycopeptide stimulation of T-cells obtained in a mouse model for rheumatoid arthritis.
Collagen induced arthritis (CIA) is the most studied animal model for rheumatoid arthritis and is associated with the MHC class II molecule Aq. T-cell recognition of a peptide from type II collagen, CII256-270, bound to Aq is a requirement for development of CIA. Lysine 264 is the major T-cell recognition site of CII256-270 and CIA is in particular associated with recognition of lysine 264 after posttranslational hydroxylation and subsequent attachment of a beta-D-galactopyranosyl moiety. In this paper we have studied the structural requirements of collagenous glycopeptides required for T-cell stimulation, as an extension of earlier studies of the recognition of the galactose moiety. Synthesis and evaluation of alanine substituted glycopeptides revealed that there are T-cells that only recognise the galactosylated hydroxylysine 264, and no other amino acid side chains in the peptide. Other T-cells also require glutamic acid 266 as a T-cell contact point. Introduction of a methylene ether isostere instead of the amide bond between residues 260 and 261 allowed weaker recognition by some, but not all, of the T-cells. Altogether, these results allowed us to propose a model for glycopeptide recognition by the T-cells, where recognition from one or the other side of the galactose moiety could explain the different binding patterns of the T-cells.
Holm
Lotta
L
Organic Chemistry, Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden.
Bockermann
Robert
R
Wellner
Erik
E
Bäcklund
Johan
J
Holmdahl
Rikard
R
Kihlberg
Jan
J
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D006020:Glycopeptides / Q000737:chemistry* / Q000276:immunology / Q000494:pharmacology*; D006825:Hybridomas / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology
D006020:Glycopeptides