Interference with the binding of a naturally processed peptide to class II alters the immunodominance of T cell epitopes in vivo.
T lymphocytes elicited in response to an immunizing Ag usually recognize only one or a few immunodominant peptides. The mechanisms governing this process are poorly understood. This study examines the consequences of peptide competition on immunodominance. Immunization of B10.A mice with the native Staphylococcus aureus nuclease protein primes T cells to the dominant 86-100 peptide presented in association with I-Ek class II molecules. To render the 86-100 peptide incapable of binding to the class II molecule, single amino acid substitutions were introduced in the native Staphylococcus aureus nuclease protein within a putative I-Ek class II binding motif. Introduction of residue changes at positions 89 and 91 in the protein prevents 86-100-specific T cell clone recognition of the protein in vitro. Competition studies demonstrate that substitutions at residues 89 or 91 decreased the I-Ek binding affinity of the 86-100 peptide. Immunization of B10.A mice with the L89F or Y91S mutant proteins does not prime T cells to the dominant 86-100 peptide; T cells are primed instead to I-Ek-restricted subdominant peptide(s) encompassed by the residues 111-135. In vitro binding studies demonstrate that both the 111-130 and 116-135 synthetic peptides compete with a labeled I-Ek-binding peptide 20-fold less efficiently than the dominant 86-100 peptide, suggesting that these subdominant peptides may be of lower binding affinity than the dominant 86-100 peptide. These results support the hypothesis that dominance is dependent on peptide binding affinity for the appropriate class II molecule and the ability to compete with other peptides, derived from the same Ag, for class II binding.
Nikcevich
K M
KM
Department of Immunology/Microbiology, Rush Presbyterian-St. Luke's Medical Center, Chicago, IL 60612.
Kopielski
D
D
Finnegan
A
A
D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins / Q000276:immunology; D000939:Epitopes; D006389:Hemagglutinins, Viral / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008836:Micrococcal Nuclease / Q000276:immunology; D008969:Molecular Sequence Data; D010455:Peptides / Q000276:immunology*; D011485:Protein Binding; D013211:Staphylococcus aureus / Q000276:immunology; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000276:immunology*
D001426:Bacterial Proteins; D000939:Epitopes; D006389:Hemagglutinins, Viral; D000949:Histocompatibility Antigens Class II; C024138:I-E-antigen; D010455:Peptides; D008836:Micrococcal Nuclease