Five HLA-DP molecules frequently expressed in the worldwide human population share a common HLA supertypic binding specificity

Abstract

Compared with DR and DQ, knowledge of the binding repertoires and specificities of HLA-DP alleles is somewhat limited. However, a growing body of literature has indicated the importance of DP-restricted responses in the context of cancer, allergy, and infectious disease. In the current study, we developed high-throughput binding assays for the five most common HLA-DPB1 alleles in the general worldwide population. Using these assays on a comprehensive panel of single-substitution analogs and large peptide libraries, we derived novel detailed binding motifs for DPB1*0101 and DPB1*0501. We also derived more detailed quantitative motifs for DPB1*0201, DPB1*0401, and DPB1*0402, which were previously characterized on the basis of sets of eluted ligands and/or limited sets of substituted peptides. Unexpectedly, all five DP molecules, originally selected only on the basis of their frequency in human populations, were found to share largely overlapping peptide motifs. Testing panels of known DP epitopes and a panel of peptides spanning a set of Phleum pratense Ags revealed that these molecules also share largely overlapping peptide-binding repertoires. This demonstrates that a previously hypothesized DP supertype extends far beyond what was originally envisioned and includes at least three additional very common DP specificities. Taken together, these DP supertype molecules are found in >90% of the human population. Thus, these findings have important implications for epitope-identification studies and monitoring of human class II-restricted immune responses.

FIGURE 1

HLA-DP binding affinity of DP epitopes and ligands. The IC₅₀ nanomolar binding capacity of known HLA-DP epitopes and ligands is shown as a function of the fraction of known epitopes and ligands that have the same or better binding affinity for their respective restricting HLA-DP allele.

FIGURE 2

HLA-DP epitopes are frequently promiscuous DP supertype binders. The percentage of peptides in a panel of known HLA-DP epitopes and ligands or a panel of 425 nonredundant peptides spanning a set of P. pratense (Phl p) pollen Ags that bound the specified number of DP molecules.

FIGURE 3

Frequency of peptides bearing the canonical DP supermotif is high among DP epitopes and promiscuous binding peptides. The percentage of peptides within various sets of peptides that bear the DP supermotif as defined herein is shown. The majority (≥69.4%) of DP-binding peptides bear the supermotif compared with a minority (22.4%) of DP nonbinders.