Subtle sequence differences in a tumour-associated peptide epitope translate into major changes in antigenicity.
Antigenicity, the ability to bind to members of repertoire of diverse immune receptors, is a concept that is poorly characterised with respect to its defining parameters. To learn more about its makeup, we have investigated the ability of two peptides with highly related sequences, derived from the tumour-associated antigen mucin-1, to recruit in vitro members from a large naïve repertoire of synthetic human antibody fragments. One of the peptides represents the epitope that is immunodominant in mice. We now demonstrate that the other peptide, which differs from the first only by a very conservative aspartate-threonine to glutamate-serine change, is much less antigenic than the first peptide. This is so despite the fact that there is no observable difference in the tendency of the two peptides to adopt a structure in solution. Furthermore, the peptides differ in their immunodominant parts and the less antigenic peptide selects for antibody fragments targeting residues outside of the epitope considered to be immunodominant in mice. We conclude that subtle sequence changes greatly, affect antigenicity and immunodominance of epitopes in this important tumour-associated antigen.
Persson
Jonas
J
Department of Immunotechnology, Lund University, P.O. Box 7031, S-22007 Lund, Sweden.
Lantto
Johan
J
Drakenberg
Torbjörn
T
Ohlin
Mats
M
D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*; D001666:Binding Sites, Antibody / Q000235:genetics; D017124:Conserved Sequence; D006801:Humans; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D051379:Mice; D018598:Minisatellite Repeats; D009077:Mucins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*; D009842:Oligopeptides / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D019151:Peptide Library
D000951:Antigens, Neoplasm; D016056:Immunodominant Epitopes; D009077:Mucins; D009363:Neoplasm Proteins; D009842:Oligopeptides; D019151:Peptide Library