HLA-DQB1 codon 57 is critical for peptide binding and recognition.
The association of specific HLA-DQ alleles with autoimmunity is correlated with discrete polymorphisms in the HLA-DQ sequence that are localized within sites suitable for peptide recognition. The polymorphism at residue 57 of the DQB1 polypeptide is of particular interest since it may play a major structural role in the formation of a salt bridge structure at one end of the peptide-binding cleft of the DQ molecules. This polymorphism at residue 57 is a recurrent feature of HLA-DQ evolution, occurring in multiple distinct allelic families, which implies a functional selection for maintaining variation at this position in the class II molecule. We directly tested the amino acid polymorphism at this site as a determinant for peptide binding and for antigen-specific T cell stimulation. We found that a single Ala-->Asp amino acid 57 substitution in an HLA-DQ3.2 molecule regulated binding of an HSV-2 VP-16-derived peptide. A complementary single-residue substitution in the peptide abolished its binding to DQ3.2 and converted it to a peptide that can bind to DQ3.1 and DQ3.3 Asp-57-positive MHC molecules. These binding studies were paralleled by specific T cell recognition of the class II-peptide complex, in which the substituted peptide abolished T cell reactivity, which was directed to the DQ3.2-peptide complex, whereas the same T cell clone recognized the substituted peptide presented by DQ3.3, a class II restriction element differing from DQ3.2 only at residue 57. This structural and functional complementarity for residue 57 and a specific peptide residue identifies this interaction as a key controlling determinant of restricted recognition in HLA-DQ-specific immune response.
Kwok
W W
WW
Virginia Mason Research Center, Seattle, Washington 98101, USA.
Domeier
M E
ME
Johnson
M L
ML
Nepom
G T
GT
Koelle
D M
DM
D000409:Alanine; D000483:Alleles; D000595:Amino Acid Sequence; D001224:Aspartic Acid; D015551:Autoimmunity; D001402:B-Lymphocytes; D001665:Binding Sites; D005075:Biological Evolution; D002461:Cell Line, Transformed; D003062:Codon; D006683:HLA-DQ Antigens / Q000737:chemistry* / Q000235:genetics*; D059866:HLA-DQ beta-Chains; D017405:Herpes Simplex Virus Protein Vmw65 / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D004854:Herpesvirus 4, Human; D006801:Humans; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D017354:Point Mutation; D011110:Polymorphism, Genetic; D013601:T-Lymphocytes / Q000276:immunology
D003062:Codon; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D017405:Herpes Simplex Virus Protein Vmw65; D010446:Peptide Fragments; D001224:Aspartic Acid; D000409:Alanine