Reversal of HLA restriction by a point mutation in an antigenic peptide.
The HLA restriction of a human T cell clone specific for residues 307-319 of influenza haemagglutinin was changed by the introduction of a point substitution in the peptide. Cells expressing HLA Dw1, DR4 Dw4, Dw13, Dw14, or Dw15 could present the natural haemagglutinin peptide to varying extents to the clone, but DR4 Dw10 could not. Replacement of glutamine-312 of the peptide with arginine produced an analogue that was recognized by the T cell clone only in the context of DR4 Dw10; neither DR1 nor any of the other DR4 alleles could present this peptide to the clone. The inability to bind either the natural or modified peptide was shown not to be the cause of the non-responsiveness. Rather, the differential stimulation of the clone appeared to arise from sequence variations between the DR alleles in residues comprising the beta-chain helix, which either affected recognition by directly contacting the T cell receptor or modified the conformation of the bound peptide. The latter effects were sufficiently subtle to modulate recognition by changing the fine details of the bound peptide but not to eliminate the capacity of the restriction element to bind the peptide.
Rothbard
J B
JB
Imperial Cancer Research Fund, London, UK.
Busch
R
R
Bal
V
V
Trowsdale
J
J
Lechler
R I
RI
Lamb
J R
JR
D000595:Amino Acid Sequence; D000956:Antigens, Viral / Q000737:chemistry / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology; D002999:Clone Cells / Q000276:immunology; D006684:HLA-DR Antigens; D006389:Hemagglutinins, Viral / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
D000956:Antigens, Viral; D006684:HLA-DR Antigens; D006389:Hemagglutinins, Viral; D010455:Peptides