Glycopeptide specificity of helper T cells obtained in mouse models for rheumatoid arthritis.
Five protected analogues of beta-D-galactosyl-(5R)-5-hydroxy-L-lysine were prepared, in which the galactosyl moiety was modified by monodeoxygenation or inversion of stereochemistry at C-4. The building blocks were used in the solid-phase synthesis of a set of glycopeptides related to the peptide fragment CII256-273 from type II collagen. Evaluation of the glycopeptides revealed that T-cell hybridomas obtained in collagen-induced arthritis (CIA), which is a common mouse model for rheumatoid arthritis, recognized the galactosyl moiety with high specificity for individual hydroxy groups. Moreover, T-cell hybridomas obtained in a humanized variant of CIA were also found to recognize the glycopeptides in an equally carbohydrate-specific manner. The results allowed the generation of models of the complexes formed between the appropriate class II major histocompatibility complex (MHC) molecule, glycopeptide, and the T-cell receptor, that is, of an interaction that is critical for the stimulation of T cells in the arthritis models. In the structural models, peptide side chains anchor the glycopeptide in pockets in the class II MHC molecule, whereas the galactosylated hydroxylysine residue forms the key contacts with the T-cell receptor. Importantly, the results also suggest that a T-cell response towards glycopeptide fragments from type II collagen could play an important role in the development of rheumatoid arthritis in humans.
Holm
Björn
B
Organic Chemistry, Department of Chemistry, Umeå University, 901 87 Umeå, Sweden.
Bäcklund
Johan
J
Recio
Miguel A F
MA
Holmdahl
Rikard
R
Kihlberg
Jan
J
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001665:Binding Sites; D024043:Collagen Type II / Q000737:chemistry / Q000276:immunology; D004195:Disease Models, Animal; D006020:Glycopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D006801:Humans; D006825:Hybridomas / Q000276:immunology; D006901:Hydroxylysine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology; D013329:Structure-Activity Relationship; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D024043:Collagen Type II; D006020:Glycopeptides; D000949:Histocompatibility Antigens Class II; D010446:Peptide Fragments; D006901:Hydroxylysine; C007817:galactosylhydroxylysine