The type 1 diabetes associated HLA-DQ8-trans dimer accomodates 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 to 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*0501) and the β-chain of HLA-DQ8 (DQB1*0302). 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.