Recognition of the HLA class II-peptide complex by T-cell receptor: reversal of major histocompatibility complex restriction of a T-cell clone by a point mutation in the peptide determinant.
Recognition of the HLA DR-peptide complex by an influenza haemagglutinin-specific T-cell clone was examined by assaying a variety of peptide analogues for their ability to be recognized. Consistent with earlier experiments arguing that the peptide blinds the restriction element in a helical conformation, acetylation of the amino terminus and amidation of the carboxy terminus of the natural determinant (residues 307-319) resulted in a peptide that exhibited both greater propensity to form a helix, as judged by circular dichroism, and the ability to stimulate the clone at concentrations approximately two orders of magnitude lower than the native sequence. The peptide was modelled into the potential antigen-combining site of HLA class II based on the ability of analogues containing point mutations to stimulate the T-cell clone. The working model was initially tested by examining the ability of Epstein-Barr-transformed B-cell lines expressing in different DR4 subtypes to present the native haemagglutinin sequence and analogues to the clone. The different alleles could be categorized as high, intermediate, or low responders based on the resulting proliferation. DR4 dw15 was a high-responding allele, dw4, 13, and 14 were intermediate-responding alleles, whereas dw10 was a low responder. Mutation of Gln to Arg at 312 in the haemagglutinin sequence converted the high and intermediate responders to non-responders, while turning the low-responding allele into an intermediate responder. Potential explanations for these effects are discussed in the context of the model of the complex between peptide and the major histocompatibility complex.
Rothbard
J B
JB
Laboratory of Molecular Immunology, Imperial Cancer Research Fund, Lincoln's Inn Fields, London, U.K.
Busch
R
R
Lechler
R
R
Trowsdale
J
J
Lamb
J R
JR
D000595:Amino Acid Sequence; D002478:Cells, Cultured; D002999:Clone Cells; D000939:Epitopes / Q000276:immunology*; D006684:HLA-DR Antigens / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010455:Peptides / Q000138:chemical synthesis / Q000276:immunology*; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D000939:Epitopes; D006684:HLA-DR Antigens; D010455:Peptides; D011948:Receptors, Antigen, T-Cell