Epitope Stealing as a Mechanism of Dominant Protection by HLA-DQ6 in Type 1 Diabetes.

Abstract

The heterozygous DQ2/8 (DQA1*05:01-DQB1*02:01/DQA1*03:01-DQB1*03:02) genotype confers the highest risk in type 1 diabetes (T1D), whereas the DQ6/8 (DQA1*02:01-DQB1*06:02/DQA1*03:01-DQB1*03:02) genotype is protective. The mechanism of dominant protection by DQ6 (DQB1*06:02) is unknown. We tested the hypothesis that DQ6 interferes with peptide binding to DQ8 by competition for islet epitope ("epitope stealing") by analysis of the islet ligandome presented by HLA-DQ6/8 and -DQ8/8 on dendritic cells pulsed with islet autoantigens preproinsulin (PPI), GAD65, and IA-2, followed by competition assays using a newly established "epitope-stealing" HLA/peptide-binding assay. HLA-DQ ligandome analysis revealed a distinct DQ6 peptide-binding motif compared with the susceptible DQ2/8 molecules. PPI and IA-2 peptides were identified from DQ6, of DQ6/8 heterozygous dendritic cells, but no DQ8 islet peptides were retrieved. Insulin B6-23, a highly immunogenic CD4 T-cell epitope in patients with T1D, bound to both DQ6 and DQ8. Yet, binding of InsB6-23 to DQ8 was prevented by DQ6. We obtained first functional evidence of a mechanism of dominant protection from disease, in which HLA molecules associated with protection bind islet epitopes in a different, competing, HLA-binding register, leading to "epitope stealing" and conceivably diverting the immune response from islet epitopes presented by disease-susceptible HLA molecules in the absence of protective HLA.

• Authors: Menno van Lummel, David T P Buis, Cherish Ringeling, Arnoud H de Ru, Jos Pool, George K Papadopoulos, Peter A van Veelen, Helena Reijonen, Jan W Drijfhout, Bart O Roep
• Journal: Diabetes (Diabetes) Vol. 68 Issue 4 Pg. 787-795 (04 2019) ISSN: 1939-327X [Electronic] United States
• PMID: 30626607 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 by the American Diabetes Association.

Chemical References

• Epitopes, T-Lymphocyte
• HLA-DQ Antigens
• HLA-DQ6 antigen

Topics

• Cell Line, Tumor
• Diabetes Mellitus, Type 1 (genetics, immunology)
• Epitopes, T-Lymphocyte (immunology)
• HLA-DQ Antigens (genetics, immunology)
• Haplotypes
• Humans