HLA-DQ polymorphisms are highly selective for peptide binding interactions.
The impact of HLA-DQ allelic polymorphism on peptide binding interactions was investigated. MHC class II binding peptides from lambda repressor (lambda R), thyroid peroxidase (TPO), and a modified poly-alanine peptide (AKY) were used in two different binding assays, one with purified DQ molecules and another with cells that expressed DQ cell surface dimers. Class II heterodimers of different combinations of DQ alpha-chain and the DQ beta-chain independently influenced specific peptide interactions. Each of the peptides tested bound differentially to DQ alleles: TPO632-645 bound test to DQ2 molecules (DQA1*0501/DQB1*0201), lambda R12-24 bound best to DQ8 molecules (DQ3.2 or DQA1*0301/DQB1*0302), and AYK bound best to DQ1 (DQA*0102/DQB*0602) and DQ7 (DQ3.1 OR DQA1*0301/DQB1*0301). However, in each case in which either the DQ alpha- or DQ beta-chain was exchanged, major alterations or reversals of this pattern of interaction were observed. The interaction of lambda R with DQ8 was highly dependent on specific sequence polymorphisms at residue 57; an Ala-->Asp substitution on the DQ beta-chain at the polymorphic codon 57 prevented peptide binding. However, Ala 57 alone was not sufficient to permit binding in other DQ allelic contexts. These studies demonstrate the critical role of specific DQ polymorphisms in establishing the nature of bound Ag and thereby influencing the potential immune repertoire. Analysis of the ability of DQ molecules to bind and present antigenic peptides should aid in understanding their role in immunity and in development of HLA-DQ-associated autoimmune disease.
Kwok
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WW
Virginia Mason Research Center, Seattle, WA 98101, USA.
Nepom
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GT
Raymond
F C
FC
D000483:Alleles; D000595:Amino Acid Sequence; D002478:Cells, Cultured; D006683:HLA-DQ Antigens / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D010455:Peptides / Q000378:metabolism*; D011110:Polymorphism, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics
D006683:HLA-DQ Antigens; D010455:Peptides