Collagen-induced arthritis (CIA) is an experimental autoimmune disease elicited in genetically susceptible strains of mice by immunization with heterologous type II collagen. This experimental disease is mediated by the immune response of both T and B cells, and susceptibility is restricted by the class II molecules of the MHC. To study the T cell determinants of bovine type II collagen (CII) that mediate the autoimmune response in H-2q mice, we have identified a cyanogen bromide fragment of bovine CII, CII(124-402), that induces arthritis in DBA/1 mice. Using an overlapping set of peptides to map the T cell response to CII(124-402), we have determined that the I-Aq-restricted T cell response to this collagen fragment is mediated by a single immunodominant antigenic determinant. Consequently, this determinant plays a central role in promoting the production of the collagen-specific Abs and the induction of CIA in H-2q mice. Characterization of this immunodominant determinant revealed that the core residues required for T cell stimulation consists of only eight amino acids and is located at amino acids 260 through 267 of bovine CII. The systematic analysis of the contribution of each of these amino acids, in conjunction with sequences of other peptides known to bind to I-Aq, have allowed us to propose a peptide binding motif for the collagen arthritis susceptibility allele, I-Aq.