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T Cell Immunity to Type II Collagen in the Biobreeding Rat: The Identification and Characterization of RT1^u-Restricted T Cell Epitopes on 1(II)¹

Michael A. Cremer^2,*,, Xiu J. Ye, Linda K. Myers, David D. Brand^*,, Edward F. Rosloniec^*, and Andrew H. Kang^*,

Research Service of ^* Veterans Affairs Medical Center and Departments of Medicine, Pediatrics, and Pathology, University of Tennessee, Memphis, TN 38104

Susceptibility to experimental collagen-induced arthritis in rodents is dependent on MHC class II elements to bind peptides from the type II collagen (CII) molecule. Although a substantial body of data has been reported in mice defining these peptide Ags, little has been reported in rats. In this study, we investigate the locations and sequences of CII peptides, which are bound by RT1^u molecules, expressed by diabetic-resistant, arthritis-susceptible Biobreeding rats, and, in turn, stimulate CII-specific T cells. By using overlapping and substituted peptide homologues of CII, we have identified and characterized an immunodominant and five subdominant epitopes on CII, which stimulate RT1^u-restricted T cell proliferation. The immunodominant epitope, CII (186–192), contains a QGPRG core sequence, which was found in a subdominant epitope CII (906–916). Similar sequences containing single conservative substitutions were identified in three other epitopes. One, CII (263–272), contained a conservatively substituted RK substitution, whereas CII (880–889) and CII (906–916) contained nonconservative substitutions, i.e., PD and RM, respectively. Homologue peptides containing these sequences stimulated T cell proliferative responses, although less intensely than peptides containing CII (186–192). Substituting QGR residues in the QGPRG core with alanine, isoleucine, or proline reduced proliferation, as did substituting flanking E and G residues at the N terminus and E at the C terminus. Collectively, these data indicate that RT1^u-restricted immunodominant and several subdominant epitopes on CII often share a QGPRG-like motif, with conservative substitutions present at either P or R positions. This motif is similar to one recognized by collagen-induced arthritis-susceptible HLA-DR1- and HLA-DR4-transgenic mice.

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