Discovery of a Selective Islet Peptidome Presented by the Highest-Risk HLA-DQ8trans Molecule

• Published in: Diabetes (New York, N.Y.) Vol. 65; no. 3; pp. 732 - 741
• Main Authors: van Lummel, Menno, van Veelen, Peter A, de Ru, Arnoud H, Pool, Jos, Nikolic, Tatjana, Laban, Sandra, Joosten, Antoinette, Drijfhout, Jan W, Gómez-Touriño, Iria, Arif, Sefina, Aanstoot, Henk J, Peakman, Mark, Roep, Bart O
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.03.2016
• Subjects: Adolescent; Adult; Antigen presentation; Autoantigens - immunology; Case-Control Studies; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Cells; Child; Dendritic Cells - immunology; Diabetes; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - immunology; Epitopes - immunology; Female; Glutamate Decarboxylase - immunology; Heterozygote; HLA-DQ Antigens - genetics; HLA-DQ Antigens - immunology; Homozygote; Humans; Immunotherapy; Insulin - immunology; Male; Molecules; Peptides; Protein Precursors - immunology; Protein Processing, Post-Translational; Receptor-Like Protein Tyrosine Phosphatases, Class 8 - immunology; T-Lymphocytes - immunology; Young Adult
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db15-1031

HLA-DQ2/8 heterozygous individuals are at far greater risk for type 1 diabetes (T1D) development by expressing HLA-DQ8trans on antigen-presenting cells compared with HLA-DQ2 or -DQ8 homozygous individuals. Dendritic cells (DC) initiate and shape adaptive immune responses by presenting HLA-epitope complexes to naïve T cells. To dissect the role of HLA-DQ8trans in presenting natural islet epitopes, we analyzed the islet peptidome of HLA-DQ2, -DQ8, and -DQ2/8 by pulsing DC with preproinsulin (PPI), IA-2, and GAD65. Quality and quantity of islet epitopes presented by HLA-DQ2/8 differed from -DQ2 or -DQ8. We identified two PPI epitopes solely processed and presented by HLA-DQ2/8 DC: an HLA-DQ8trans-binding signal-sequence epitope previously identified as CD8 T-cell epitope and a second epitope that we previously identified as CD4 T-cell epitope with increased binding to HLA-DQ8trans upon posttranslational modification. IA-2 epitopes retrieved from HLA-DQ2/8 and -DQ8 DC bound to HLA-DQ8cis/trans. No GAD65 epitopes were eluted from HLA-DQ. T-cell responses were detected against the novel islet epitopes in blood from patients with T1D but scantly detected in healthy donor subjects. We report the first PPI and IA-2 natural epitopes presented by highest-risk HLA-DQ8trans. The selective processing and presentation of HLA-DQ8trans-binding islet epitopes provides insight in the mechanism of excessive genetic risk imposed by HLA-DQ2/8 heterozygosity and may assist immune monitoring of disease progression and therapeutic intervention as well as provide therapeutic targets for immunotherapy in subjects at risk for T1D.