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    Insulin granule antigens and T-cell resistance to immune regulation: novel disease pathways and biomarkers in type 1 diabetes

    Mahmoud Tarayrah


    Lundi 14 juin 2021 à 14h

    Institut Cochin
    Salle Rosalind Franklin
    En visioconférence pour le public

    Directrice de thèse : Sylvaine You

    Equipe : Diabète de type 1 : tolérance, biomarqueurs et thérapies T cellulaires

    Département : Endocrinologie, Métabolisme et Diabète (EMD)


    Résumé :

    Type 1 diabetes (T1D) is an autoimmune disease characterized by the selective destruction of insulin-producing β cells by autoreactive T cells. Our Laboratory documented that CD8+ T cells recognizing β-cell antigens circulate at similar frequencies in T1D and healthy donors. This finding underpins the existence of a universal state of 'benign autoimmunity'. Only in T1D, islet-reactive T cells get activated, migrate to the pancreas and destroy β cells. During my PhD, I addressed the mechanisms of progression to T1D by focusing on two complementary processes: 1) the recognition of novel autoantigens driving pathogenic CD8+ T-cell responses; and 2) the resistance of effector T cells to the immune regulation mediated by the suppressive cytokine TGF-β.

    1) HLA peptidomics analysis of β cells exposed to inflammatory cytokines revealed an enriched presentation of peptides from secretory granule proteins, notably secretogranin 5 (SCG5), proconvertase-2 (PCSK2) and urocortin-3 (UCN3), whose role in T1D pathogenesis remained unknown. I identified CD8+ T cells recognizing these proteins in the pancreatic islets of the non-obese diabetic (NOD) mouse model of T1D, and showed that they efficiently transfer diabetes into NOD/scid recipients. These data, combined with the recognition of these novel antigens by HLA-A2 and A3-restricted CD8+ T cells from T1D and healthy donors, underscore the relevance of insulin granules in T1D pathogenesis.

    2) Functional studies in both human and mouse repeatedly demonstrated that T cells from autoimmune donors are refractory to TGF-β regulation, compared to control subjects (poor inhibition of activation and proliferation; reduced capacity to upregulated PD-1 expression and to convert naïve CD4+ T cells into Foxp3+ Tregs). I correlated this defect with an overexpression of the inhibitory TGF-β signaling molecule Smad7, paralleled by an impaired phosphorylation of the activatory Smad2/3. In vivo Smad7 blockade, pharmacologically with specific antisense oligonucleotides or genetically in CD4-Cre/Smad7fl/fl mice, restored T-cell sensitivity to TGF-β and prevented diabetes development.

    As a whole, this work unveiled new cellular and molecular players in the switch from benign autoimmunity to T1D, which may translate into novel T1D biomarkers and therapeutics.


    Keywords: Type 1 diabetes, immune tolerance, TGF-β, β cells, autoantigens, biomarkers, immunotherapie