Beta-amino acid scan of a class I major histocompatibility complex-restricted alloreactive T-cell epitope.
An HLA-B27-restricted self-octapeptide known to react with an alloreactive T-cell receptor has been modified by systematic substitution of a beta-amino acid for the natural alpha-amino acid residue, over the whole length of the parent epitope. All modified peptides were shown to bind to recombinant HLA-B*2705 and induce stable major histocompatibility complex-peptide complexes, but with some variation depending on the position of the beta-amino acid on the peptide sequence. Alteration of the natural peptide sequence at the two N-terminal positions (positions 1 and 2) decreases binding affinity and thermodynamic stability of the refolded complex, but all other positions (from position 3 to the C-terminal residue) were insensitive to the beta-amino acid substitution. All modified peptides were recognized by an alloreactive T-cell clone specific for the parent epitope with decreased efficiency, to an extent dependent of the position that was modified. Furthermore, the introduction of a single beta-amino acid at the first two positions of the modified peptide was shown to be sufficient to protect them against enzymatic cleavage. Thus, beta-amino acids represent new interesting templates for alteration of T-cell epitopes to design either synthetic vaccines of T-cell receptor antagonists.
Reinelt
S
S
Department of Applied Biosciences, Swiss Federal Institute of Technology, Wintherthurerstrasse 190, CH-8057 Zürich, Switzerland.
Marti
M
M
Dédier
S
S
Reitinger
T
T
Folkers
G
G
de Castro
J A
JA
Rognan
D
D
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002851:Chromatography, High Pressure Liquid; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry* / Q000378:metabolism; D015235:HLA-B Antigens / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D011485:Protein Binding; D017510:Protein Folding; D011994:Recombinant Proteins; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D018984:Epitopes, T-Lymphocyte; D015235:HLA-B Antigens; D008024:Ligands; D011994:Recombinant Proteins