Differences in peptide binding of DR11 and DR13 microvariants demonstrate the power of minor variation in generating DR functional diversity.
The influence of subtle HLA diversification on antigen binding was explored using murine L-cell transfectants expressing alleles in the DR11/DR13 family and a panel of peptides. The levels of binding among this family of DR microvariants were as diverse as the levels of binding among distantly related DR molecules. Even a single amino acid difference between allelic products had a profound effect on peptide binding. Specific amino acid substitutions, generated using site-directed mutagenesis to alter polymorphic residues at DR beta 32, 37, 57, 58, 67, 71, 86, demonstrated that a specific change within the context of a single DR molecule differed in its effect on the binding of specific peptides. In addition, a specific amino acid substitution had a differential effect on the binding level of a peptide to different DR molecules. Each polymorphic amino acid appeared to play a role in the binding of some peptide. Studies using the amino-terminal portion of the invariant chain CLIP peptide suggested that this peptide may offer varying degrees of competition in the binding of the cellular peptide pool in cells expressing different DR molecules. Finally, the results obtained with two strain-specific peptides from an immunodominant region of a malarial parasite show differential binding to two DR13 molecules, suggesting that immune pressure may promote parasite diversity. A dynamic interaction may exist between pathogens and the immune system shaping the HLA profile in a population. Thus even subtle diversification of the HLA molecules, possibly pathogen driven, can have a substantial effect on peptide binding and immune recognition.
Hurley
C K
CK
Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC 20007, USA.
Steiner
N
N
D000483:Alleles; D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000737:chemistry; D000940:Antigenic Variation; D002460:Cell Line; D018076:DNA, Complementary / Q000235:genetics; D018014:Gene Transfer Techniques; D006684:HLA-DR Antigens / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D059810:HLA-DR Serological Subtypes; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000276:immunology; D011485:Protein Binding / Q000235:genetics / Q000276:immunology
D000911:Antibodies, Monoclonal; D018076:DNA, Complementary; D006684:HLA-DR Antigens; D059810:HLA-DR Serological Subtypes; C080766:HLA-DR11 antigen