HLA‐DRβ chain residue 86 controls DRαβ dimer stability

Major histocompatibility complex class II molecules exist in two forms, which can be distinguished on the basis of their stability in sodium dodecyl sulfate (SDS) as SDS‐stable and SDS‐unstable αβ dimers. The ratio of stable vs. unstable αβ dimers varies between murine H‐2 alleles and isotypes, but the molecular basis for this observation is unknown. Here we show that for the human HLA‐DRB1 and HLA‐DRB3 gene products this ratio is controlled by the valine/glycine dimorphism at position 86. Haplotypes coding for DRβ chains with a valine at position 86 express higher numbers of stable dimers compared to similar haplotypes expressing DRβ chains with a glycine at that position. Reverse‐phase high‐performance liquid chromatography analysis of iodinated peptides, which were eluted from DR dimers with either a DRB1*1101 or a DRB1*1104 β chain which differ only at position 86, indicated that these DR dimers contain (partially) distinct sets of peptides. The valine/glycine dimorphism is highly conserved, present in most HLA‐DR alleles and influences peptide‐binding. Analysis of the occurrence of theVal86 and the Gly86 gene products revealed that these are not equally present in the population. Depending on the DR specificity either the Val86 of Gly86 allelic variant is favored. Thus, the natural, highly conserved dimorphism at HLA‐DR β chain position 86 influences peptide selection. The dimorphism is therefore likely to influence antigen presentation and forms the molecular basis for the observed differences in stability of Val86‐ and Gly86‐containing DR dimers in the presence of SDS.