The peptide-binding motif of HLA-DR8 shares important structural features with other type 1 diabetes-associated alleles

Abstract

The objective of this study was to characterize the peptide-binding motif of the major histocompatibility complex (MHC) class II HLA-DR8 molecule included in the type 1 diabetes-associated haplotype DRB1*0801-DQA1*0401/DQB1*0402 (DR8-DQ4), and compare it with that of other diabetes-associated MHC class II alleles; DR8-bound peptides were eluted from an HLA-DR homozygous lymphoblastoid cell line. The repertoire was characterized by peptide sequencing using a LTQ ion trap mass spectrometer coupled to a multidimensional liquid chromatography system. After validation of the spectra identification, the definition of the HLA-DR8 peptide-binding motif was achieved from the analysis of 486 natural ligands, based on serial alignments of all possible HLA-DR-binding cores. The DR8 motif showed a strong similarity with the peptide-binding motifs of other MHC class II diabetes-associated alleles, HLA-DQ8 and H-2 I-A g7 . Similar to HLA-DQ8 and H-2 I-A g7 , HLA-DR8 preferentially binds peptides with an acidic residue at position P9 of the binding core, indicating that DR8 is the susceptibility component of the DR8-DQ4 haplotype. Indeed, some DR8 peptides were identical to peptides previously identified as DQ8-or I-A g7 ligands, and several diabetes-specific peptides associated with DQ8 or I-A g7 could theoretically bind to HLA-DR8. These data further strengthen the association of HLA-DR8 with type I diabetes.

Differential Binding of Pyruvate Dehydrogenase Complex-E2 Epitopes by DRB1*08:01 and DRB1*11:01 Is Predicted by Their Structural Motifs and Correlates with Disease Risk

“…However, when a polar or acidic residue was anchored in pocket 6, this preference was reduced. Similar preferences were recently reported by Muixi et al, who inferred a binding motif for DR8 based on an aligned matrix of 228 unique sequences that were eluted from HLA-DR sequences purified from a HLA-DR8 homozygous lymphoblastoid cell line (30). Their findings indicated a preference for basic and small aliphatic residues in pocket 4, basic residues in pocket 6, and acidic residues in pocket 9.…”

Multicomponent Injectable Hydrogels for Antigen‐Specific Tolerogenic Immune Modulation

“…[5–7] Additionally, BDC2.5 T cells may have relevance to human disease, since they recognize peptides in the context of the MHC class II I-A g7 , whose peptide binding pocket bears structural similarities with class II human leukocyte antigen (HLA) variants that are associated with susceptibility to type 1 diabetes in patients. [30] Here, we administer pore-forming gels delivering GM-CSF and BDC peptide, [31] a peptide antigen mimotope recognized by BDC2.5 T cells, in NOD mice with the aim of modulating the BDC antigen-specific Treg population. Subcutaneous administration of these gels leads to localized antigen delivery and antigen-specific T cell expansion in the lymph nodes (LN) draining the gels.…”

Composition of the HLA‐DR‐associated human thymus peptidome

“…2A), with an average length of 15 aa (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27), within the standard MHC-II size range. The peptides were classified as part of different cellular compartments and then grouped according to their putative degradation pathways.…”

“…The data were then analysed with peptides previously eluted from different B-cell lines, including (i) 402 sequences from HLA-DR8 published by our group [17] and (ii) HLA-DR3 natural ligands from the SYFPEITHY database (n = 131) [18]. The last series was included as a specific DR3 control because all thymus samples analysed were HLA-DR3…”