Identification of MHC class II and TCR binding residues in the type II collagen immunodominant determinant mediating collagen-induced arthritis.
Collagen-induced arthritis (CIA), an autoimmune arthritis model, is elicited by the immunization of genetically susceptible strains of mice with type II collagen (CII). We have analyzed the molecular interactions that occur during the presentation of the immunodominant determinant within CII(257-270) by the murine class II susceptibility allele, I.Aq. Utilizing a soluble I-A binding assay and clonally distinct CII-specific T cells, we have identified the residues that control the ability of the CII(257-270) peptide to bind to I-Aq and those that interact with the TCR. In competitive binding assays with a panel of analog peptides, only two residues within CII(257-270) were found to participate in the binding of this peptide to I-Aq, residues 260 (Ile) and 263 (Phe). When these substitutions were combined into a single peptide, no binding of the peptide to I-Aq could be detected. Although no other substitutions decreased the binding affinity of the peptides, substitution of several amino acid residues lying outside of the determinant core increased the peptide's affinity for I-Aq and in some instances greatly enhanced the potency of the peptide in stimulating T cells. In antigen presentation assays, clonotypic variation in the recognition of several analog peptides indicated that residues 261, 262, 264, 266, and 267 are likely TCR contact sites. Since residue 266 interacts with the TCR and is the only residue in this determinant that differs between chick/bovine CII and mouse CII, these data indicate that immunity to the autoantigen may play a role in this model.
Rosloniec
E F
EF
Department of Medicine, University of Tennessee, Memphis 38163, USA.
Whittington
K B
KB
Brand
D D
DD
Myers
L K
LK
Stuart
J M
JM
D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000276:immunology*; D001665:Binding Sites; D002460:Cell Line; D003094:Collagen / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D016056:Immunodominant Epitopes; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology
D000949:Histocompatibility Antigens Class II; D016056:Immunodominant Epitopes; D011948:Receptors, Antigen, T-Cell; D003094:Collagen