Journal Article

DKFZ-2021-00212

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Peptides Derived From Insulin Granule Proteins Are Targeted by CD8+ T Cells Across MHC Class I Restrictions in Humans and NOD Mice.

Azoury, M. E. ; Tarayrah, M. ; Afonso, G. ; Pais, A. ; Colli, M. L. ; Maillard, C. ; Lavaud, C. ; Alexandre-Heymann, L. ; Gonzalez-Duque, S. ; Verdier, Y. ; Vinh, J. ; Pinto, S.DKFZ* ; Buus, S. ; Dubois-Laforgue, D. ; Larger, E. ; Beressi, J.-P. ; Bruno, G. ; Eizirik, D. L. ; You, S. ; Mallone, R.

2020
Assoc. Alexandria, Va

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Please use a persistent id in citations: doi:10.2337/db20-0013

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.

Keyword(s): Adult (MeSH) ; Alternative Splicing (MeSH) ; Animals (MeSH) ; CD8-Positive T-Lymphocytes (MeSH) ; Case-Control Studies (MeSH) ; Chromogranins: genetics (MeSH) ; Chromogranins: metabolism (MeSH) ; Computer Simulation (MeSH) ; Data Mining (MeSH) ; Diabetes Mellitus, Type 1: genetics (MeSH) ; Diabetes Mellitus, Type 1: metabolism (MeSH) ; Epitopes (MeSH) ; Female (MeSH) ; Gene Expression Regulation (MeSH) ; HLA-A3 Antigen (MeSH) ; Humans (MeSH) ; Insulin (MeSH) ; Male (MeSH) ; Mice (MeSH) ; Mice, Inbred NOD (MeSH) ; Neuroendocrine Secretory Protein 7B2: genetics (MeSH) ; Neuroendocrine Secretory Protein 7B2: metabolism (MeSH) ; Protein Binding (MeSH) ; RNA, Messenger: genetics (MeSH) ; Urocortins: genetics (MeSH) ; Urocortins: metabolism (MeSH) ; Young Adult (MeSH) ; Chromogranins ; Epitopes ; HLA-A3 Antigen ; Insulin ; Neuroendocrine Secretory Protein 7B2 ; RNA, Messenger ; Ucn3 protein, mouse ; Urocortins

Note: Division of Developmental Immunology

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Contributing Institute(s):

1. Entwicklungsimmunologie (D090 ; D090)

Research Program(s):

1. 314 - Tumor immunology (POF3-314) (POF3-314)

Appears in the scientific report 2020

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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