DISRUPTION OF THE DETERMINANT HIERARCHY ON A SELF-MHC PEPTIDE - CONCOMITANT TOLERANCE INDUCTION TO THE DOMINANT DETERMINANT AND PRIMING TO THE CRYPTIC SELF-DETERMINANT

The presentation of self-peptides in a self-restricted manner plays a critical role in the complex positive and negative selective process of T cell recognition of self-determinants. The population of determinants comprises (i) a dominant set which is efficiently presented and induces clonal elimination or inactivation of the corresponding autoreactive T cells, and (ii) a cryptic set which is not processed efficiently enough to reach the threshold of presentation to make an impact on the T cell repertoire during thymic selection. Here we have studied a self-MHC peptide, L(d) 61-85, which as shown in earlier work was able to induce vigorous T cell proliferation in syngeneic animals. Despite the fact that this peptide as a whole is 'cryptic', the fine specificity of the class II restricted response was complex, in that there were three distinct and overlapping T cell determinants: the dominant determinant, L(d) 65-80, flanked by two cryptic determinants, L(d) 61-15 and L(d) 73-85, all of which compete for stimulating in vivo autoreactive T cell proliferative responses. The hierarchy of these determinants bears an interesting relationship to tolerance. L(d) 61-85 or L(d) 61-80 priming induces proliferation only to L(d) 65-80; likewise, tolerance induction to L(d) 61-80 prevents elicitation of a subsequent response to L(d) 61-80 or L(d) 65-80 in the local lymph nodes. However, in the L(d) 61-80 tolerant mice, in vivo challenge with L(d) 61-80 induces a strong T cell proliferative response directed towards cryptic L(d) 61-75. Apparently, while tolerance had been induced to the dominant self-determinant, simultaneous priming occurred to the cryptic determinant, making it visible and immunogenic. Tolerance induction had reversed the hierarchy of dominance, a consequence that has important ramifications for autoimmunity.