Conventional and Neo-Antigenic Peptides Presented by β Cells Are Targeted by Circulating Naïve CD8+ T Cells in Type 1 Diabetic and Healthy Donors

Sergio Gonzalez-Duque 1, 2, 3 Marie Eliane Azoury 1, 2, 4 Maikel Colli 5 Georgia Afonso 1, 2, 4 Jean-Valery Turatsinze 5 Laura Nigi 6 Ana Inés Lalanne 1, 2, 4 Guido Sebastiani 6 Alexia Carré 1, 2, 4 Sheena Pinto 7 Slobodan Culina 1, 2, 4 Noémie Corcos 1, 2, 4 Marco Bugliani 8 Marc Marchetti 8 Mathieu Armanet 9 Marc Diedisheim 1, 2, 10, 4, 11 Bruno Kyewski 7 Lars Steinmetz 12, 13 Søren Buus 14 Sylvaine You 2, 1, 4 Daniele Dubois-Laforgue 2, 1, 10, 4, 11 Etienne Larger 2, 1, 10, 4, 11 Jean-Paul Beressi 15 Graziella Bruno 16 Francesco Dotta 6 Raphael Scharfmann 1, 2, 4 Decio Eizirik 5 Yann Verdier 17 Joelle Vinh 17 Roberto Mallone 1, 2, 10, 4, 11, *
* Corresponding author
1 IC UM3 (UMR 8104 / U1016) - Institut Cochin
2 USPC - Université Sorbonne Paris Cité
3 ESPCI ParisTech
4 UPD5 - Université Paris Descartes - Paris 5
5 Medical Faculty - Center for Diabetes Research and Welbio [Brussels, Belgium]
6 Diabetes Unit - Department of Medicine, Surgery and Neuroscience [Siena, Italy]
7 Division of Developmental Immunology [Heidelberg, Germany]
8 Department of Clinical and Experimental Medicine [Pisa, Italy]
9 Cell Therapy Unit [AP-HP Hôpital Saint-Louis]
10 Service de diabétologie [CHU Cochin]
11 CHU Cochin [AP-HP]
12 School of Medicine - Department of Genetics and Stanford Genome Technology Center [Stanford, CA, USA]
13 Genome Biology Unit [Heidelberg, Germany]
14 Department of Immunology and Microbiology [Copenhagen]
15 Service de Diabétologie [CH Versailles André Mignot, Le Chesnay]
16 Department of Medical Sciences [Turin, Italy]
17 SMBP - Laboratoire de Spectrométrie de Masse Biologique & Protéomique
Abstract : Although CD8+ T-cell-mediated autoimmune β cell destruction occurs in type 1 diabetes (T1D), the target epitopes processed and presented by β cells are unknown. To identify them, we combined peptidomics and transcriptomics strategies. Inflammatory cytokines increased peptide presentation in vitro, paralleling upregulation of human leukocyte antigen (HLA) class I expression. Peptide sources featured several insulin granule proteins and all known β cell antigens, barring islet-specific glucose-6-phosphatase catalytic subunit-related protein. Preproinsulin yielded HLA-A2-restricted epitopes previously described. Secretogranin V and its mRNA splice isoform SCG5-009, proconvertase-2, urocortin-3, the insulin gene enhancer protein ISL-1, and an islet amyloid polypeptide transpeptidation product emerged as antigens processed into HLA-A2-restricted epitopes, which, as those already described, were recognized by circulating naive CD8+ T cells in T1D and healthy donors and by pancreas-infiltrating cells in T1D donors. This peptidome opens new avenues to understand antigen processing by β cells and for the development of T cell biomarkers and tolerogenic vaccination strategies.
Keywords : autoimmunity human leukocyte antigen (HLA) preproinsulin epitope antigen proconvertase urocortin secretogranin type 1 diabetes transpeptidation
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https://www.hal.inserm.fr/inserm-01918834
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Submitted on : Monday, November 12, 2018 - 12:46:10 AM
Last modification on : Tuesday, January 21, 2020 - 11:16:03 AM
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Sergio Gonzalez-Duque, Marie Eliane Azoury, Maikel Colli, Georgia Afonso, Jean-Valery Turatsinze, et al.. Conventional and Neo-Antigenic Peptides Presented by β Cells Are Targeted by Circulating Naïve CD8+ T Cells in Type 1 Diabetic and Healthy Donors. Cell Metabolism, Elsevier, 2018, 28 (6), pp.946-960. ⟨10.1016/j.cmet.2018.07.007⟩. ⟨inserm-01918834⟩

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