The impact of DR3 microvariation on peptide binding: The combinations of specific drβ residues critical to binding differ for different peptides

HLA-DR molecules are a group of highly polymorphic glycoprotein heterodimers that present peptide antigens to T lymphocytes for immune surveillance. To assess the significance of limited polymorphism on the functional differentiation of DR molecules, the binding of several immunogenic peptides to the DR3 microvariants DR(,β1^*0301) and DR(,β1^*0302)] and to mutants of these DR3 molecules was examined. This analysis has shown that each residue (DRβ26, DRβ28, DRβ47, and DRβ86), which differentiates these two DR3 molecules, contributes to their functional distinction and that the relative contribution of each residue varies for different peptide/DR3 complexes. For example, DRβ28 and DRβ86 controlled the mycobacterium tuberculosis 65-kD heat shock protein peptides 3–13 and 4–15 (HSP) binding specificity to DR(a,βl*0301). HSP does not bind to DR(,β1^*0302)], whereas DRβ26, DRβ28, and DRβ86 controlled the influenza hemagglutinin peptide 306–318 (HA) binding specificity to DR(,β1^*0302). HA does not bind to DR(,β1^*0301).] In comparison, DRβ86 alone controlled the binding level difference of sperm whale myoglobin peptide 132–151 (SWM) and of myelin basic protein peptide 152–170 (MBP) both bind to DR(,β1^*0301) at levels five times greater than to DR(,β1^*0302)] to the DR3 molecules. Although not critical, additional DRβ residues influenced the binding level of individual peptides to each of the DR3 molecules and, again, the combinations of these residues differed for different peptide/DR3 complexes. These data showed that individual DR residues vary in their relative contribution to the interaction between a specific DR molecule and different peptides and that limited polymorphism can create substantial differences in the peptide binding profiles among DR molecules.