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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

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posted on 14.09.2020 by Ada Admin, 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
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 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 neo-epitopes, 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 orthologues 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.

Funding

This work was performed within the Département Hospitalo-Universitaire (DHU) AutHorS and supported by Legs Borel; a PhD fellowship of the Ile-de-France CORDDIM and Aide aux Jeunes Diabétiques (to S.G.D.); a Master fellowship from the Société Francophone di Diabète (to A.P.); and by grants from the JDRF (2-SRA-2016-164-Q-R), the Fondation Francophone pour la Recherche sur le Diabète, the EFSD/JDRF/Lilly European Programme in Type 1 Diabetes Research 2015, the Agence Nationale de la Recherche (ANR-19-CE15-0014-01), the Fondation pour la Recherche Médicale (EQU20193007831), the Association pour la Recherche sur le Diabète, to R.M.; Inserm-Transfert Proof of Concept 2018, to S.Y.; Welbio/FRFS, Wallonie, Belgium (WELBIO-CR-2019C-04), to D.L.E.; and Conseil Régional d’Ile-de-France, to J.V.. R.M. and D.L.E. received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreements 115797 and 945268 (INNODIA and INNODIA HARVEST), which receive support from the EU Horizon 2020 program, the European Federation of Pharmaceutical Industries and Associations, JDRF, and the Leona M. and Harry B. Helmsley Charitable Trust.

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