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Immunology and Transplantation

Peptides Derived From Insulin Granule Proteins Are Targeted by CD8+ T Cells Across MHC Class I Restrictions in Humans and NOD Mice

  1. Marie Eliane Azoury1,
  2. Mahmoud Tarayrah1,
  3. Georgia Afonso1,
  4. Aurore Pais1,
  5. Maikel L. Colli2,
  6. Claire Maillard1,
  7. Cassandra Lavaud1,
  8. Laure Alexandre-Heymann1,3,
  9. Sergio Gonzalez-Duque1,4,
  10. Yann Verdier4,
  11. Joelle Vinh4,
  12. Sheena Pinto5,
  13. Soren Buus6,
  14. Danièle Dubois-Laforgue1,3,
  15. Etienne Larger1,3,
  16. Jean-Paul Beressi7,
  17. Graziella Bruno8,
  18. Decio L. Eizirik2,
  19. Sylvaine You1 and
  20. Roberto Mallone1,3⇑
  1. 1Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France
  2. 2Université Libre de Bruxelles Center for Diabetes Research and Welbio, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium
  3. 3Assistance Publique Hôpitaux de Paris, Hôpitaux Universitaires de Paris Centre-Université de Paris, Cochin Hospital, Service de Diabétologie et Immunologie Clinique, Paris, France
  4. 4École Supérieure de Physique et de Chimie Industrielles Paris, Université Paris Sciences et Lettres, Spectrométrie de Masse Biologique et Protéomique, CNRS USR3149, Paris, France
  5. 5Division of Developmental Immunology, Deutsches Krebsforschungszentrum, Heidelberg, Germany
  6. 6Laboratory of Experimental Immunology, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
  7. 7Service de Diabétologie, Centre Hospitalier de Versailles André Mignot, Le Chesnay, France
  8. 8Department of Medical Sciences, University of Turin, Turin, Italy
  1. Corresponding author: Roberto Mallone, roberto.mallone{at}inserm.fr
  1. M.E.A. and M.T. contributed equally to this work.

Diabetes 2020 Dec; 69(12): 2678-2690. https://doi.org/10.2337/db20-0013
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Abstract

The antigenic peptides processed by β-cells and presented through surface HLA class I molecules are poorly characterized. Each HLA variant (e.g., the most common being HLA-A2 and HLA-A3) carries some peptide-binding specificity. Hence, features that, despite these specificities, remain shared across variants may reveal factors favoring β-cell immunogenicity. Building on our previous description of the HLA-A2/A3 peptidome of β-cells, we analyzed the HLA-A3–restricted peptides targeted by circulating CD8+ T cells. Several peptides were recognized by CD8+ T cells within a narrow frequency (1–50/106), which was similar in donors with and without type 1 diabetes and harbored variable effector/memory fractions. These epitopes could be classified as conventional peptides or neoepitopes, generated either via peptide cis-splicing or mRNA splicing (e.g., secretogranin-5 [SCG5]–009). As reported for HLA-A2–restricted peptides, several epitopes originated from β-cell granule proteins (e.g., SCG3, SCG5, and urocortin-3). Similarly, H-2Kd–restricted CD8+ T cells recognizing the murine orthologs of SCG5, urocortin-3, and proconvertase-2 infiltrated the islets of NOD mice and transferred diabetes into NOD/scid recipients. The finding of granule proteins targeted in both humans and NOD mice supports their disease relevance and identifies the insulin granule as a rich source of epitopes, possibly reflecting its impaired processing in type 1 diabetes.

Footnotes

  • See accompanying article, p. 2575.

  • This article contains supplementary material online at https://doi.org/10.2337/figshare.12899315.

  • Received January 5, 2020.
  • Accepted August 31, 2020.
  • © 2020 by the American Diabetes Association
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Peptides Derived From Insulin Granule Proteins Are Targeted by CD8+ T Cells Across MHC Class I Restrictions in Humans and NOD Mice
Marie Eliane Azoury, Mahmoud Tarayrah, Georgia Afonso, Aurore Pais, Maikel L. Colli, Claire Maillard, Cassandra Lavaud, Laure Alexandre-Heymann, Sergio Gonzalez-Duque, Yann Verdier, Joelle Vinh, Sheena Pinto, Soren Buus, Danièle Dubois-Laforgue, Etienne Larger, Jean-Paul Beressi, Graziella Bruno, Decio L. Eizirik, Sylvaine You, Roberto Mallone
Diabetes Dec 2020, 69 (12) 2678-2690; DOI: 10.2337/db20-0013

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Peptides Derived From Insulin Granule Proteins Are Targeted by CD8+ T Cells Across MHC Class I Restrictions in Humans and NOD Mice
Marie Eliane Azoury, Mahmoud Tarayrah, Georgia Afonso, Aurore Pais, Maikel L. Colli, Claire Maillard, Cassandra Lavaud, Laure Alexandre-Heymann, Sergio Gonzalez-Duque, Yann Verdier, Joelle Vinh, Sheena Pinto, Soren Buus, Danièle Dubois-Laforgue, Etienne Larger, Jean-Paul Beressi, Graziella Bruno, Decio L. Eizirik, Sylvaine You, Roberto Mallone
Diabetes Dec 2020, 69 (12) 2678-2690; DOI: 10.2337/db20-0013
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