TY - JOUR
T1 - Islet-derived EATP fuels autoreactive CD8+ T cells and facilitates the onset of type 1 diabetes
AU - Tezza, Sara
AU - Nasr, Moufida Ben
AU - D'Addio, Francesca
AU - Vergani, Andrea
AU - Usuelli, Vera
AU - Falzoni, Simonetta
AU - Bassi, Roberto
AU - Dellepiane, Sergio
AU - Fotino, Carmen
AU - Rossi, Chiara
AU - Maestroni, Anna
AU - Solini, Anna
AU - Corradi, Domenico
AU - Giani, Elisa
AU - Mameli, Chiara
AU - Bertuzzi, Federico
AU - Pezzolesi, Marcus G.
AU - Wasserfall, Clive H.
AU - Atkinson, Mark A.
AU - Füchtbauer, Ernst Martin
AU - Ricordi, Camillo
AU - Folli, Franco
AU - Virgilio, Francesco Di
AU - Pileggi, Antonello
AU - Dhe-Paganon, Sirano
AU - Zuccotti, Gian Vincenzo
AU - Fiorina, Paolo
N1 - Publisher Copyright:
© 2018 by the American Diabetes Association.
PY - 2018/10
Y1 - 2018/10
N2 - 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.
AB - 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.
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U2 - 10.2337/db17-1227
DO - 10.2337/db17-1227
M3 - Article
C2 - 30065030
AN - SCOPUS:85054774069
VL - 67
SP - 2038
EP - 2053
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 10
ER -