Islet-Derived eATP Fuels Autoreactive CD8(+) T Cells and Facilitates the Onset of Type 1 Diabetes
| Autor: | Anna Solini, Vera Usuelli, Domenico Corradi, Roberto Bassi, Paolo Fiorina, Antonello Pileggi, Sara Tezza, Clive Wasserfall, Carmen Fotino, Chiara Rossi, Ernst-Martin Füchtbauer, Mark A. Atkinson, Federico Bertuzzi, Francesca D'Addio, Andrea Vergani, Camillo Ricordi, Sirano Dhe-Paganon, Elisa Giani, Chiara Mameli, Franco Folli, Anna Maestroni, Simonetta Falzoni, Sergio Dellepiane, Gian Vincenzo Zuccotti, Francesco Di Virgilio, Marcus G. Pezzolesi, Moufida Ben Nasr |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
receptor Endocrinology Diabetes and Metabolism Priming (immunology) Autoimmunity CD8-Positive T-Lymphocytes medicine.disease_cause Lymphocyte Activation release NO 03 medical and health sciences Mice Insulin-secretion extracellular atp oxidized atp autocrine transplant inhibitor disease 0302 clinical medicine Adenosine Triphosphate Downregulation and upregulation Mice Inbred NOD Internal Medicine medicine Cytotoxic T cell Animals Humans Receptor NOD mice Mice Inbred BALB C Chemistry Flow Cytometry In vitro Cell biology 030104 developmental biology Diabetes Mellitus Type 1 Mutation Female Receptors Purinergic P2X7 Immunology and Transplantation CD8 030215 immunology |
| Zdroj: | Tezza, S, Ben Nasr, M, D'Addio, F, Vergani, A, Usuelli, V, Falzoni, S, Bassi, R, Dellepiane, S, Fotino, C, Rossi, C, Maestroni, A, Solini, A, Corradi, D, Giani, E, Mameli, C, Bertuzzi, F, Pezzolesi, M G, Wasserfall, C H, Atkinson, M A, Füchtbauer, E M, Ricordi, C, Folli, F, Di Virgilio, F, Pileggi, A, Dhe-Paganon, S, Zuccotti, G V & Fiorina, P 2018, ' Islet-Derived eATP Fuels Autoreactive CD8+ T Cells and Facilitates the Onset of Type 1 Diabetes ', Diabetes, vol. 67, no. 10, pp. 2038-2053 . https://doi.org/10.2337/db17-1227 |
| Popis: | Extracellular ATP (eATP) activates T cells by engaging the P2X7R receptor. We identified two loss-of-function P2X7R mutations that are protective against type 1 diabetes (T1D) and thus hypothesized that eATP/P2X7R signaling may represent an early step in T1D onset. Specifically, we observed that in patients with newly diagnosed T1D, P2X7R is upregulated on CD8+ effector T cells in comparison with healthy control subjects. eATP is released at high levels by human/murine islets in vitro in high-glucose/inflammatory conditions, thus upregulating P2X7R on CD8+ T cells in vitro. P2X7R blockade with oxidized ATP reduces the CD8+ T cell–mediated autoimmune response in vitro and delays diabetes onset in NOD mice. Autoreactive CD8+ T-cell activation is highly dependent upon eATP/P2X7R-mediated priming, while a novel sP2X7R recombinant protein abrogates changes in metabolism and the autoimmune response associated with CD8+ T cells. eATP/P2X7R signaling facilitates the onset of autoimmune T1D by fueling autoreactive CD8+ cells and therefore represents a novel targeted therapeutic for the disorder. |
| Databáze: | OpenAIRE |
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