Allele-specific B pocket transplant in class I major histocompatibility complex protein changes requirement for anchor residue at P2 of peptide.
To investigate the role of an anchoring pocket in allele-specific peptide presentation by a major histocompatibility complex class I molecule, we "transplanted" a B pocket from HLA-A*0201 into HLA-B*2705 by site-directed mutagenesis. The resulting protein, designated B27.A2B, binds a different set of endogenous peptides than B*2705 as evidenced by complete loss of allorecognition as well as restored expression in the antigen processing-defective mutant cell line T2. B27.A2B also fails to present an HLA-B27-restricted influenza virus peptide [nucleoprotein (383-391)] to cytotoxic T lymphocytes (CTLs). However, substitution of leucine, the predominant P2 anchor residue in A*0201-restricted peptides, for arginine, the P2 anchor in nucleoprotein-(383-391) and other B*2705-restricted peptides, restores recognition of B27.A2B by the same B*2705-restricted peptide-specific CTLs. These results demonstrate that a dominant polymorphic pocket in a class I molecule, through interaction with the anchor residue of an antigenic peptide, can distinguish among peptides differing by only a single amino acid and thus determine the allelic specificity of peptide presentation.
Colbert
R A
RA
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill 27599.
Rowland-Jones
S L
SL
McMichael
A J
AJ
Frelinger
J A
JA
D000483:Alleles; D000595:Amino Acid Sequence; D000938:Antigen-Presenting Cells / Q000276:immunology; D001120:Arginine / Q000276:immunology; D002460:Cell Line; D000939:Epitopes / Q000276:immunology; D005805:Genes, MHC Class I / Q000235:genetics / Q000276:immunology*; D015796:HLA-B27 Antigen / Q000235:genetics / Q000276:immunology*; D008239:Lysine / Q000276:immunology; D008969:Molecular Sequence Data; D009154:Mutation; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D016601:RNA-Binding Proteins; D013329:Structure-Activity Relationship; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014758:Viral Core Proteins / Q000276:immunology
D000939:Epitopes; D015796:HLA-B27 Antigen; C048842:NP protein, Influenza A virus; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins; D010446:Peptide Fragments; D016601:RNA-Binding Proteins; D014758:Viral Core Proteins; D001120:Arginine; D008239:Lysine