title: Type 1 diabetes-associated HLA-DQ8 transdimer accommodates a unique peptide repertoire.
abstract: HLA-DQ2 and HLA-DQ8 are strongly predisposing haplotypes for type 1 diabetes (T1D). Yet HLA-DQ2/8 heterozygous individuals have a synergistically increased risk compared with HLA-DQ2 or HLA-DQ8 homozygote subjects that may result from the presence of a transdimer formed between the α-chain of HLA-DQ2 (DQA1*05:01) and the β-chain of HLA-DQ8 (DQB1*03:02). We generated cells exclusively expressing this transdimer (HLA-DQ8trans), characterized its peptide binding repertoire, and defined a unique transdimer-specific peptide binding motif that was found to be distinct from those of HLA-DQ2 and HLA-DQ8. This motif predicts an array of peptides of islet autoantigens as candidate T cell epitopes, many of which selectively bind to the HLA transdimer, whereas others bind to both HLA-DQ8 and transdimer with similar affinity. Our findings provide a molecular basis for the association between HLA-DQ transdimers and T1D and set the stage for rational testing of potential diabetogenic peptide epitopes.
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Menno
authors.initials: M
authors.lastname: van Lummel
authors.forename: Peter A
authors.initials: PA
authors.lastname: van Veelen
authors.forename: Arnaud
authors.initials: A
authors.lastname: Zaldumbide
authors.forename: Arnoud
authors.initials: A
authors.lastname: de Ru
authors.forename: George M C
authors.initials: GM
authors.lastname: Janssen
authors.forename: Antonis K
authors.initials: AK
authors.lastname: Moustakas
authors.forename: George K
authors.initials: GK
authors.lastname: Papadopoulos
authors.forename: Jan W
authors.initials: JW
authors.lastname: Drijfhout
authors.forename: Bart O
authors.initials: BO
authors.lastname: Roep
authors.forename: Frits
authors.initials: F
authors.lastname: Koning
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D002460:Cell Line; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D020022:Genetic Predisposition to Disease; D006683:HLA-DQ Antigens / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D010455:Peptides / Q000378:metabolism*; D011485:Protein Binding
chemical_list: D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; C109756:HLA-DQ8 antigen; D010455:Peptides