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PMID: 22184118 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Type 1 diabetes-associated HLA-DQ8 transdimer accommodates a unique peptide repertoire.

The Journal of biological chemistry ·Vol. 287 ·No. 12 ·2012-03-16 ·Pages 9514-24

van Lummel M, van Veelen PA, Zaldumbide A, de Ru A, Janssen GM, Moustakas AK, Papadopoulos GK, Drijfhout JW, Roep BO, Koning F

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.

MeSH Terms
Amino Acid Motifs Amino Acid Sequence Cell Line Diabetes Mellitus, Type 1/genetics,metabolism Dimerization Genetic Predisposition to Disease HLA-DQ Antigens/chemistry,genetics,metabolism Humans Molecular Sequence Data Peptides/metabolism Protein Binding
Chemicals
HLA-DQ Antigens HLA-DQ2 antigen HLA-DQ8 antigen Peptides
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
van Lummel Menno
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
van Veelen Peter A
Zaldumbide Arnaud
de Ru Arnoud
Janssen George M C
Moustakas Antonis K
Papadopoulos George K
Drijfhout Jan W
Roep Bart O
Koning Frits
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Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
1083-351X
DOI
10.1074/jbc.M111.313940
Published
2012-03-16
Epub
2011-00-19
Pages
9514-24
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC3308765
Subset
IM
External Links
PubMed source DOI: 10.1074/jbc.M111.313940 PMC Full Text View journal details
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