Human Population Frequently Expressed in the Worldwide Repertoires of Six HLA-DQ Molecules Divergent Motifs but Overlapping Binding

Knowledge of the binding repertoires and specificities of HLA-DQ molecules is somewhat limited and contradictory, partly because of the scarcity of reports addressing some of the most common molecules and possibly because of the diversity of the techniques used. In this paper, we report the development of high-throughput binding assays for the six most common DQ molecules in the general worldwide population. Using comprehensive panels of single substitution analogs of specific ligands, we derived detailed binding motifs for DQA1*0501/DQB1*0301, DQA1*0401/DQB1*0402, and DQA1*0101/DQB1*0501 and more detailed motifs for DQA1*0501/DQB1*0201, DQA1*0301/DQB1*0302, and DQA1*0102/DQB1*0602, previously characterized on the basis of sets of eluted ligands and/or limited sets of substituted peptides. In contrast to what has previously been observed for DR and DP molecules, DQ motifs were generally less clearly defined in terms of chemical specificity and, strikingly, had little overlap with each other. However, testing a panel of peptides spanning a set of Phleum pratense Ags, and panels of known DQ epitopes, revealed a surprisingly significant and substantial overlap in the repertoire of peptides bound by these DQ molecules. Although the mechanism underlying these apparently contradictory findings is not clear, it likely reflects the peculiar mode of interaction between DQ (and not DR or DP) molecules and their peptide ligands. Because the DQ molecules studied are found in >85% of the general human population, these findings have important implications for epitope identification studies and monitoring of DQ-restricted immune responses. T cells recognize MHC–epitope complexes (1–4). MHC molecules are extremely polymorphic, with several thousand of different variants known in humans (5–8). Much of the observed polymorphism is concentrated in residues experimentally known or modeled to line the peptide-binding groove or form the specific pockets that engage the amino acid side chains of the pep-tide ligand. Addressing multiple MHC-binding specificities is therefore required to allow coverage of the general human population. This issue of population coverage is further complicated by the fact that different MHC types are expressed at dramatically different frequencies in different ethnicities. Thus, without careful consideration , an epitope set could result in ethnically biased population coverage and decreased applicability for any diagnostic, immuno-prophylactic, or immunotherapeutic applications. One means of circumventing these problems relies on the selection of epitopes restricted by multiple MHC types. Alternatively, epitope sets representing the most common molecules present in each patient population will have to be selected and studied. In the case of HLA class I, previous …