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, 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)
Benichou
G
G
Department of Microbiology and Molecular Genetics, UCLA 90024.
Fedoseyeva
E
E
Olson
C A
CA
Geysen
H M
HM
McMillan
M
M
Sercarz
E E
EE
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
D001324:Autoantigens; D000939:Epitopes; D010455:Peptides