Islet-Derived eATP Fuels Autoreactive CD8+ T Cells and Facilitates the Onset of Type 1 Diabetes

• Published in: Diabetes (New York, N.Y.) Vol. 67; no. 10; pp. 2038 - 2053
• Main Authors: Tezza, Sara, Ben Nasr, Moufida, D’Addio, Francesca, Vergani, Andrea, Usuelli, Vera, Falzoni, Simonetta, Bassi, Roberto, Dellepiane, Sergio, Fotino, Carmen, Rossi, Chiara, Maestroni, Anna, Solini, Anna, Corradi, Domenico, Giani, Elisa, Mameli, Chiara, Bertuzzi, Federico, Pezzolesi, Marcus G., Wasserfall, Clive H., Atkinson, Mark A., Füchtbauer, Ernst-Martin, Ricordi, Camillo, Folli, Franco, Di Virgilio, Francesco, Pileggi, Antonello, Dhe-Paganon, Sirano, Zuccotti, Gian Vincenzo, Fiorina, Paolo
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.10.2018
• Subjects: Adenosine Triphosphate - analogs & derivatives; Adenosine Triphosphate - metabolism; Adenosine Triphosphate - pharmacology; Animals; Autoimmunity - genetics; Autoimmunity - physiology; CD8-Positive T-Lymphocytes - metabolism; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - metabolism; Female; Flow Cytometry; Humans; Immunology and Transplantation; Lymphocyte Activation - drug effects; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Mutation - genetics; Receptors, Purinergic P2X7 - genetics; Receptors, Purinergic P2X7 - metabolism
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db17-1227

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.