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.
Islet-derived EATP fuels autoreactive CD8+ T cells and facilitates the onset of type 1 diabetes / Tezza, S.; Nasr, M. B.; 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.; Fuchtbauer, E. -M.; Ricordi, C.; Folli, F.; Virgilio, F. D.; Pileggi, A.; Dhe-Paganon, S.; Zuccotti, G. V.; Fiorina, P.. - In: DIABETES. - ISSN 0012-1797. - 67:10(2018), pp. 2038-2053. [10.2337/db17-1227]
Islet-derived EATP fuels autoreactive CD8+ T cells and facilitates the onset of type 1 diabetes
Bassi R.;Corradi D.;Mameli C.;Folli F.;
2018-01-01
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
