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 newly diagnosed T1D patients, P2X7R is upregulated on CD8+ effector T cells in comparison to healthy controls. 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 (oATP) 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.
|Autori:||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 Guy; 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|
|Titolo:||Islet-Derived eATP Fuels Autoreactive CD8+ Cells and Facilitates the Onset of Type 1 Diabetes|
|Anno del prodotto:||2018|
|Digital Object Identifier (DOI):||10.2337/db17-1227|
|Appare nelle tipologie:||1.1 Articolo in rivista|