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• W4385471978 endingPage "104740" @default.
• W4385471978 startingPage "104740" @default.
• W4385471978 abstract "BackgroundTo resist the autoimmune attack characteristic of type 1 diabetes, insulin producing pancreatic β cells need to evade T-cell recognition. Such escape mechanisms may be conferred by low HLA class I (HLA-I) expression and upregulation of immune inhibitory molecules such as Programmed cell Death Ligand 1 (PD-L1).MethodsThe expression of PD-L1, HLA-I and CXCL10 was evaluated in the human β cell line, ECN90, and in primary human and mouse pancreatic islets. Most genes were determined by real-time RT-PCR, flow cytometry and Western blot. Activator and inhibitor of the AKT signaling were used to modulate PD-L1 induction. Key results were validated by monitoring activity of CD8+ Jurkat T cells presenting β cell specific T-cell receptor and transduced with reporter genes in contact culture with the human β cell line, ECN90.FindingsIn this study, we identify tryptophan (TRP) as an agonist of PD-L1 induction through the AKT signaling pathway. TRP also synergistically enhanced PD-L1 expression on β cells exposed to interferon-γ. Conversely, interferon-γ-mediated induction of HLA-I and CXCL10 genes was down-regulated upon TRP treatment. Finally, TRP and its derivatives inhibited the activation of islet-reactive CD8+ T cells by β cells.InterpretationCollectively, our findings indicate that TRP could induce immune tolerance to β cells by promoting their immune evasion through HLA-I downregulation and PD-L1 upregulation.FundingDutch Diabetes Research Foundation, DON Foundation, the Laboratoire d’Excellence consortium Revive (ANR-10-LABX-0073), Agence Nationale de la Recherche (ANR-19-CE15-0014-01), Fondation pour la Recherche Médicale (EQ U201903007793–EQU20193007831), Innovative Medicines Initiative INNODIA and INNODIA HARVEST, Aides aux Jeunes Diabetiques (AJD) and Juvenile Diabetes Research Foundation Ltd (JDRF)." @default.
• W4385471978 created "2023-08-02" @default.
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• W4385471978 date "2023-09-01" @default.
• W4385471978 modified "2023-10-14" @default.
• W4385471978 title "Tryptophan metabolism promotes immune evasion in human pancreatic β cells" @default.
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