Abstract
Human leukocyte antigen (HLA)-DR15 is a haplotype associated with multiple sclerosis. It contains the two DRB* genes DRB1*1501 (DR2b) and DRB5*0101 (DR2a). The reported anchor motif of the corresponding HLA-DR molecules was determined in 1994 based on a small number of peptide ligands and binding assays. DR2a could display a set of peptides complementary to that presented by DR2b or, alternatively, a similar peptide repertoire but recognized in a different manner by T cells. It is known that DR2a and DR2b share some peptide ligands, although the degree of similarity of their associated peptidomes remains unclear. In addition, the contribution of each molecule to the global peptide repertoire presented by the HLA-DR15 haplotype has not been evaluated. We used mass spectrometry to analyze the peptide pools bound to DR2a and DR2b, identifying 169 and 555 unique peptide ligands of DR2a and DR2b, respectively. The analysis of these sets of peptides allowed the refinement of the corresponding binding motifs revealing novel anchor residues that had been overlooked in previous analyses. Moreover, the number of shared ligands between both molecules was low, indicating that DR2a and DR2b present complementary peptide repertoires to T cells. Finally, our analysis suggests that, quantitatively, both molecules contribute to the peptide repertoire presented by cells expressing the HLA-DR15 haplotype.
Highlights
Human leukocyte antigen (HLA)-DP, -DQ, and -DR are membrane heterodimeric glycoproteins, composed by two chains, α and β, encoded in the class II region of the human major histocompatibility complex (MHC) or HLA
We have addressed three main questions: first, the fine-mapping of the anchor motifs of DR2a and DR2b by the identification of natural ligands bound to these allotypes; second, the degree of overlap of the peptide repertoires bound to these two HLA-DR molecules (DR2a and DR2b); and third, the contribution of DR2a and DR2b to the peptide repertoire presented on the cell surface
Peptides derived from some heterogeneous nuclear ribonucleoproteins were considered as background contaminants on the basis of their particular features and of our previous observations [similar peptides had been found in previous analysis of other unrelated HLA-II and HLA-I molecules [32]]
Summary
Human leukocyte antigen (HLA)-DP, -DQ, and -DR are membrane heterodimeric glycoproteins, composed by two chains, α and β, encoded in the class II region of the human major histocompatibility complex (MHC) or HLA. Four different HLA-DP and HLA-DQ molecules are present in heterozygous cells, as each polymorphic α chain can interact with either polymorphic β chain. In the case of HLA-DR, the gene encoding the HLA-DRα subunit is dimorphic (and both forms are functionally equivalent). Only two different heterodimers are usually expressed. Some haplotypes include two functional HLA-DRB genes, allowing the expression of four different molecules in heterozygous individuals, all of them carrying the same HLA-DRα chain. The DR3, DR11, DR12, DR13, and DR14 haplotypes express DRB1
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