HLA-B7–Restricted Islet Epitopes Are Differentially Recognized in Type 1 Diabetic Children and Adults and Form Weak Peptide-HLA Complexes

  1. Roberto Mallone1,2,4
  1. 1INSERM, U986, DeAR Lab Avenir, Cochin-Saint Vincent de Paul Hospital, Paris, France
  2. 2Faculté de Médecine, Paris Descartes University, Sorbonne Paris Cité, Paris, France
  3. 3Laboratory of Experimental Immunology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
  4. 4Department of Diabetology, Cochin-Hôtel Dieu Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
  5. 5Department of Pediatric Endocrinology and Diabetes, Robert Debré Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
  6. 6Paris 7 Denis Diderot University, Paris, France
  7. 7Departement of Internal Medicine, University of Turin, Turin, Italy
  8. 8INSERM, CIC BT505, Centre d’Investigation Clinique de Vaccinologie Cochin Pasteur, Cochin-Hôtel Dieu Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
  1. Corresponding author: Roberto Mallone, roberto.mallone{at}inserm.fr.

Abstract

The cartography of β-cell epitopes targeted by CD8+ T cells in type 1 diabetic (T1D) patients remains largely confined to the common HLA-A2 restriction. We aimed to identify β-cell epitopes restricted by the HLA-B7 (B*07:02) molecule, which is associated with mild T1D protection. Using DNA immunization on HLA-B7–transgenic mice and prediction algorithms, we identified GAD and preproinsulin candidate epitopes. Interferon-γ (IFN-γ) enzyme-linked immunospot assays on peripheral blood mononuclear cells showed that most candidates were recognized by new-onset T1D patients, but not by type 2 diabetic and healthy subjects. Some epitopes were highly immunodominant and specific to either T1D children (GAD530–538; 44% T cell–positive patients) or adults (GAD311–320; 38%). All epitopes displayed weak binding affinity and stability for HLA-B7 compared with HLA-A2–restricted ones, a general feature of HLA-B7. Single-cell PCR analysis on β-cell–specific (HLA-B7 tetramer–positive) T cells revealed uniform IFN-γ and transforming growth factor-β (TGF-β) mRNA expression, different from HLA-A2–restricted T cells. We conclude that HLA-B7–restricted islet epitopes display weak HLA-binding profiles, are different in T1D children and adults, and are recognized by IFN-γ+TGF-β+CD8+ T cells. These features may explain the T1D-protective effect of HLA-B7. The novel epitopes identified should find valuable applications for immune staging of HLA-B7+ individuals.

Footnotes

  • Received February 8, 2012.
  • Accepted April 10, 2012.

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  1. Diabetes vol. 61 no. 10 2546-2555
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