In the course of the study of MBP/EAE system, we have been successful in establishing a prototypic model of """"""""molecular-mimicry"""""""" or antigenic crossreactivity at the T cell clonal level. In this system, T cell lines and clones specific for Ac1-9 of myelin basic protein (MBP) recognize determinants on chimeric peptides made up of different regions of the MBP sequence, 7-11:35-47 and 7-11:35-44, which have only a 3 amino acid overlap with Ac1-9. This system offers the possibility of examining in detail T cell crossreactivity at the clonal level, and such provide new insights pertaining to recognition of antigen-MHC complexes by T cells. Important questions to be answered are (a) whether T cell crossreactivity could occur in the absence of any significant sequence homology (b) whether the mimicry peptide will bind MHC in a homologous fashion (c) and what is the relationship between crossreactivity and TcR receptor gene expression. In this study we will define the critical amino acids residues on the chimeric peptides and determine whether they are TcR contact or MHC binding residues. Additionally, we will analyze the similarity of binding of the Ac1-9 and chimeric peptides to MHC. The relationship between TcR gene usage and crossreactivity will be examined. Lastly, we will study the hindering effect of the 2 additional amino terminal residues (R-5 and P-6) in 5-11:35-44 and 5-11:35-47. Antigenic crossreactivity has been frequently evoked as a mechanism which plays both a central role in the shaping of the T cell repertoire and in initiating autoimmune diseases. Our model should provide a clear insight into the mechanism underlying T cell mimicry at the clonal level.
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