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 el icited by the immunization of genetically susceptible strains of mice with type LI collagen (CII). We have analyzed the molecular interactio ns that occur during the presentation of the immunodominant determinan t within CII(257-270) by the murine class II susceptibility allele, I- A(q). Utilizing a soluble I-A binding assay and clonally distinct CII- specific T cells, we have identified the residues that control the abi lity of the CII(257-270) peptide to bind to I-A(q) and those that inte ract with the TCR. In competitive binding assays with a panel of analo g peptides, only two residues within CII(257-270) were found to partic ipate in the binding of this peptide to I-A(q), residues 260 (De) and 263 (Phe). When these substitutions were combined into a single peptid e, no binding of the peptide to I-A(q) could be detected. Although no other substitutions decreased the binding affinity of the peptides, su bstitution of several amino acid residues lying outside of the determi nant core increased the peptide's affinity for I-A(q) and in some inst ances greatly enhanced the potency of the peptide in stimulating T cel ls. In antigen presentation assays, clonotypic variation in the recogn ition of several analog peptides indicated that residues 261, 262, 264 , 266, and 267 are likely TCR contact sites. Since residue 266 interac ts with the TCR and is the only residue in this determinant that diffe rs between chick/bovine CII and mouse CII, these data indicate that im munity to the autoantigen may play a role in this model. (C) 1996 Acad emic Press, Inc.