T cell response of I-Aq mice to self type II collagen: meshing of the binding motif of the I-Aq molecule with repetitive sequences results in autoreactivity to multiple epitopes

Type II collagen (CII) is of immunological interest because of itsrepetitive structure and properties as an autoantigen. The mouse gene hasrecently been cloned, thus enabling T cell-defined epitopes to beidentified. Multiple novel epitopes on mouse CII are here detected in theautoreactive T cell response. The major response is directed to an epitopewith residues 707-721 located on the CB10 fragment. Some 25 other epitopesare also recognized, including the autologous homologue of the 256-270epitope which dominates in the response to foreign collagen. The cellsreactive with mouse collagen peptides were of Th1 type, as judged byrelease of IFN-gamma. No significant reactivity was detected to mouse CIIpeptides during ongoing disease. Alignment of the mouse epitopes revealed asequence motif with characteristic side chains at residues P1, P4 and P7,and to a lesser extent at P5, within a nonamer core sequence. Binding ofthese epitopes was simulated in a computer model of the I-Aq molecule,where peptides with anchor residues at P1, P4 and P7 were indeed found tofit the binding groove best. The spacing of pockets and the fine structureof the binding surface of the I-Aq molecule meshes with the repetitivestructure of the collagen (X-Y-Gly), thus providing a likely explanationfor the occurrence of multiple epitopes. Comparison with human DR bindingmotifs showed that the I-Aq motif resembles most closely that of the DR4subtypes which predispose for rheumatoid arthritis.