INTRAMOLECULAR MIMICRY - IDENTIFICATION AND ANALYSIS OF 2 CROSS-REACTIVE T-CELL EPITOPES WITHIN A SINGLE PROTEIN

The recognition of peptide Ags by T cells through the TCR has exquisit e specificity. Cross-reactive T cell responses have been described; ho wever, the structural basis for these responses is not known. We show that two peptides derived from the same protein can exhibit sufficient structural homology, despite minimal structural identity, to elicit c ross-reactive T cell responses. In addition, we explore the structural basis for cross-reactivity. T cell hybridomas recognizing PiM and PiZ allelic forms of human alpha(1)-antitrypsin (hAAT) each recognized bo th PiM 205-220 and PiM 335-350. These two peptides possessed primary s equence identity at only two of 16 am ino acid residues. Cross-reactiv e peptides also exhibited homology at the bulk T cell level because ly mph node T cells primed with one peptide proliferated to the other pep tide in vitro. Critical amino acids for the responding T cells were de termined, and the core was transferred into the less reactive peptide in an attempt to increase homology by increasing sequence identity. In terestingly, as identity increased, homology decreased: peptides with the least primary sequence identity appeared most homologous to the T cells. These results have important implications for understanding the development of autoimmune diseases, and imply that minimal obvious pr imary sequence identity may be sufficient to initiate cross-reactive T cell responses. The ability of structurally dissimilar peptides to mi mic each other when bound to a class II MHC molecule may also be impor tant to the understanding of T development and autoimmunity.