A single amino acid substitution in HLA-A2 can alter the selection of the cytotoxic T lymphocyte repertoire that responds to influenza virus matrix peptide 55-73.
Previous studies have demonstrated that certain amino acid substitutions in the alpha two domain at positions 152 and 156 in the alpha two helix of the HLA-A2 molecule can affect presentation of the influenza virus matrix peptide M1 55-73 without abolishing binding of the M1 peptide. HLA-A2.1-restricted M1 55-73 peptide-specific CTL lines obtained from almost all HLA-A2.1+ individuals fail to recognize the M1 peptide presented by site-directed mutants of HLA-A2 that have either a Val----Ala or Val----Gln substitution at position 152 or a Leu----Trp substitution at position 156. Only one HLA-A2+ individual (donor Q66, HLA-A2,-B53,-B63) has been found who is able to generate a unique repertoire of HLA-A2-restricted M1 peptide-specific CTL that can recognize peptide presented by HLA-A2 mutants with either an Ala or Gln substitution at position 152 or a Trp substitution at position 156. These Q66 M1 peptide-specific CTL could be selected by stimulation with M1 peptide-pulsed transfectants that express the mutant HLA-A2 gene with the Trp substitution at 156. To determine if the presence of the unique CTL repertoire could be attributed to a variant HLA-A2 molecule in Q66, sequences were determined from polymerase chain reaction-amplified segments of the HLA-A2 RNA. Two different HLA-A2 genes were found expressed in Q66 cells: one is identical to HLA-A2.1 and the other is identical to HLA-A2.2F (Gln----Arg at position 43, Val----Leu at position 95, and Leu----Trp at position 156). These results demonstrate that a different CTL repertoire specific for HLA-A2 plus the M1 55-73 peptide is generated in an individual that expresses both HLA-A2.1 and HLA-A2.2F compared to individuals who express HLA-A2.1 alone, and that the unique repertoire can be selected by the presence of an HLA-A2 molecule with a single amino acid substitution at position 156.
Shimojo
N
N
Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892.
Cowan
E P
EP
Engelhard
V H
VH
Maloy
W L
WL
Coligan
J E
JE
Biddison
W E
WE
D000328:Adult; D000595:Amino Acid Sequence; D000938:Antigen-Presenting Cells / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology; D001483:Base Sequence; D002460:Cell Line; D003601:Cytotoxicity Tests, Immunologic; D000939:Epitopes / Q000276:immunology; D015234:HLA-A Antigens / Q000235:genetics* / Q000276:immunology; D015789:HLA-A2 Antigen; D006801:Humans; D009980:Influenza A virus / Q000276:immunology*; D008969:Molecular Sequence Data; D009154:Mutation; D010446:Peptide Fragments / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000145:classification / Q000276:immunology*; D014763:Viral Matrix Proteins / Q000276:immunology*
D000956:Antigens, Viral; D000939:Epitopes; D015234:HLA-A Antigens; D015789:HLA-A2 Antigen; D010446:Peptide Fragments; D014763:Viral Matrix Proteins