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 o f T cell recognition of self-determinants. The population of determina nts comprises (i) a dominant set which is efficiently presented and in duces clonal elimination or inactivation of the corresponding autoreac tive T cells, and (ii) a cryptic set which is not processed efficientl y enough to reach the threshold of presentation to make an impact on t he T cell repertoire during thymic selection. Here we have studied a s elf-MHC peptide, L(d) 61-85, which as shown in earlier work was able t o induce vigorous T cell proliferation in syngeneic animals. Despite t he fact that this peptide as a whole is 'cryptic', the fine specificit y of the class II restricted response was complex, in that there were three distinct and overlapping T cell determinants: the dominant deter minant, L(d) 65-80, flanked by two cryptic determinants, L(d) 61-15 an d L(d) 73-85, all of which compete for stimulating in vivo autoreactiv e 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, toleran ce induction to L(d) 61-80 prevents elicitation of a subsequent respon se to L(d) 61-80 or L(d) 65-80 in the local lymph nodes. However, in t he 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 se lf-determinant, simultaneous priming occurred to the cryptic determina nt, making it visible and immunogenic. Tolerance induction had reverse d the hierarchy of dominance, a consequence that has important ramific ations for autoimmunity.