CE15 - Immunologie, Infectiologie et Inflammation

Granules secretory proteins: novel autoimmune targets and biomarkers in type 1 diabetes – GRASP

Submission summary

Type 1 diabetes (T1D) results from the destruction of pancreatic islet beta cells by autoimmune CD8+ T cells. We hypothesize that beta cells play a key role in their own autoimmune demise, by increasing their immune visibility and vulnerability. Our analysis of the beta-cell peptidome identified novel antigenic proteins derived from the insulin granules. In particular, secretogranin-5 (SCG5), proconvertase-2 (PCSK2) and urocortin-3 (UCN3) were recognized by human circulating CD8+ T cells and islet-infiltrating CD8+ T cells in the Non-Obese Diabetic (NOD) mouse model of T1D. These T cells are diabetogenic upon in vivo transfer, supporting their pathological role. Two features shared with (pro)insulin may explain this pathogenicity: 1) these granule proteins are released through exocytosis in the bloodstream, thus potentially sensitizing the immune system at distance; 2) they are produced as precursors, and their processing is impaired in T1D, as reflected by increased secretion of unprocessed proinsulin.
Our objectives are to investigate:
#1. Pathogenicity of SCG5, PCSK2 and UCN3. We will address this: 1A) in the NOD mouse, by characterizing CD8+ T cells reactive to these granule proteins and their pathogenicity in T-cell receptor-retrogenic NOD mice; and 1B) in the human, by using CD8+ T-cell clones/transductants recognizing these antigens, to verify their in vitro capacity to be stimulated by dendritic cells exposed to the ?-cell secretome and to destroy ? cells.
#2. SCG5, PCSK2 and UCN3 as novel biomarkers of beta-cell stress and autoimmunity. We will analyze whether these granule proteins: 2A) are increasingly released as pro-proteins (like proinsulin) by beta cells exposed to metabolic or inflammatory stress; and 2B) elicit autoantibody responses in T1D patients.
This project will 1) clarify novel pathogenic mechanisms of T1D, i.e. how beta cells may contribute to their own vulnerability; and 2) provide new biomarkers for T1D diagnosis and staging.

Project coordinator

Madame Sylvaine YOU (Institut national de la sante et de la recherche medicale)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

Institut national de la sante et de la recherche medicale

Help of the ANR 264,194 euros
Beginning and duration of the scientific project: January 2023 - 36 Months

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