title: Disruption of the determinant hierarchy on a self-MHC peptide: concomitant tolerance induction to the dominant determinant and priming to the cryptic self-determinant.
abstract: 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, Ld 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, Ld 65-80, flanked by two cryptic determinants, Ld 61-75 and Ld 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. Ld 61-85 or Ld 61-80 priming induces proliferation only to Ld 65-80; likewise, tolerance induction to Ld 61-80 prevents elicitation of a subsequent response to Ld 61-80 or Ld 65-80 in the local lymph nodes. However, in the Ld 61-80 tolerant mice, in vivo challenge with Ld 61-80 induces a strong T cell proliferative response directed towards cryptic Ld 61-75.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Microbiology and Molecular Genetics, UCLA 90024.
authors.forename: G
authors.initials: G
authors.lastname: Benichou
authors.forename: E
authors.initials: E
authors.lastname: Fedoseyeva
authors.forename: C A
authors.initials: CA
authors.lastname: Olson
authors.forename: H M
authors.initials: HM
authors.lastname: Geysen
authors.forename: M
authors.initials: M
authors.lastname: McMillan
authors.forename: E E
authors.initials: EE
authors.lastname: Sercarz
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000276:immunology; D000939:Epitopes / Q000276:immunology*; D008285:Major Histocompatibility Complex / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D010455:Peptides / Q000276:immunology*; D017634:Self Tolerance / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D001324:Autoantigens; D000939:Epitopes; D010455:Peptides