Epitope glycosylation plays a critical role for T cell recognition of type II collagen in collagen-induced arthritis.
Immunization of mice with type II collagen (CII) leads to collagen-induced arthritis (CIA), a model for rheumatoid arthritis. T cell recognition of CII is believed to be a critical step in CIA development. We have analyzed the T cell determinants on CII and the TCR used for their recognition, using twenty-nine T cell hybridomas derived from C3H.Q and DBA/1 mice immunized with rat CII. All hybridomas were specific for the CII(256-270) segment. However, posttranslational modifications (hydroxylation and variable O-linked glycosylation) of the lysine at position 264 generated five T cell determinants that were specifically recognized by different T cell hybridoma subsets. TCR sequencing indicated that each of the five T cell epitopes selected its own TCR repertoire. The physiological relevance of this observation was shown by in vivo antibody-driven depletion of TCR Valpha2-positive T cells, which resulted in an inhibition of the T cell proliferative response in vitro towards the non-modified CII(256-270), but not towards the glycosylated epitope. Most hybridomas (20/29) specifically recognized CII(256-270) glycosylated with a monosaccharide (beta-D-galactopyranose). We conclude that this glycopeptide is immunodominant in CIA and that posttranslational modifications of CII create new T cell determinants that generate a diverse TCR repertoire.
Department of Cell and Molecular Biology, Lund University, Sweden. Alexandre.Corthay@inflam.lu.se
A
A
Corthay
J
J
Bäcklund
J
J
Broddefalk
E
E
Michaëlsson
T J
TJ
Goldschmidt
J
J
Kihlberg
R
R
Holmdahl
D000595:Amino Acid Sequence; D000818:Animals; D001168:Arthritis / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000209:etiology / Q000235:genetics / Q000276:immunology; D001483:Base Sequence; D003094:Collagen / Q000737:chemistry / Q000276:immunology*; D004247:DNA / Q000235:genetics; D004195:Disease Models, Animal; D006031:Glycosylation; D006825:Hybridomas / Q000276:immunology; D007114:Immunization; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008811:Mice, Inbred DBA; D008969:Molecular Sequence Data; D015394:Molecular Structure; D051381:Rats; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*
D016056:Immunodominant Epitopes; D016693:Receptors, Antigen, T-Cell, alpha-beta; D003094:Collagen; D004247:DNA