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- Title
Islet-Derived eATP Fuels Autoreactive CD8<sup>+</sup> T Cells and Facilitates the Onset of Type 1 Diabetes.
- Authors
Tezza, Sara; Vergani, Andrea; Bassi, Roberto; Dellepiane, Sergio; Nasr, Moufida Ben; D'Addio, Francesca; Usuelli, Vera; Fiorina, Paolo; Pezzolesi, Marcus G.; Wasserfall, Clive H.; Atkinson, Mark A.; F'chtbauer, Ernst-Martin; Folli, Franco; Dhe-Paganon, Sirano; Ben Nasr, Moufida; Pezzolesi, Marcus Guy; Maestroni, Anna; Zuccotti, Gian Vincenzo; Füchtbauer, Ernst-Martin; Falzoni, Simonetta
- Abstract
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.
- Subjects
ADENOSINE triphosphate receptors; CD8 antigen; T cells; TYPE 1 diabetes; AUTOIMMUNE disease treatment; INFLAMMATION treatment; THERAPEUTICS
- Publication
Diabetes, 2018, Vol 67, Issue 10, p2038
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db17-1227