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

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DOI

  • Sara Tezza, Boston Children's Hospital
  • ,
  • Moufida Ben Nasr, Boston Children's Hospital, Luigi Sacco Hospital
  • ,
  • Francesca D'Addio, Boston Children's Hospital, Luigi Sacco Hospital
  • ,
  • Andrea Vergani, Boston Children's Hospital
  • ,
  • Vera Usuelli, Boston Children's Hospital, Luigi Sacco Hospital
  • ,
  • Simonetta Falzoni, University of Ferrara
  • ,
  • Roberto Bassi, Boston Children's Hospital
  • ,
  • Sergio Dellepiane, Boston Children's Hospital
  • ,
  • Carmen Fotino, Miami University
  • ,
  • Chiara Rossi, University of Pisa
  • ,
  • Anna Maestroni, Luigi Sacco Hospital
  • ,
  • Anna Solini, University of Pisa
  • ,
  • Domenico Corradi, degli Studi di Parma
  • ,
  • Elisa Giani, Luigi Sacco Hospital
  • ,
  • Chiara Mameli, Luigi Sacco Hospital
  • ,
  • Federico Bertuzzi, ASST Grande Ospedale Metropolitano Niguarda
  • ,
  • Marcus G. Pezzolesi, University of Utah
  • ,
  • Clive H. Wasserfall, University of Florida College of Medicine
  • ,
  • Mark A. Atkinson, University of Florida College of Medicine
  • ,
  • Ernst Martin Füchtbauer
  • Camillo Ricordi, Miami University
  • ,
  • Franco Folli, Universita degli Studi di Milano, Ospedali San Paolo e San Carlo Borromeo
  • ,
  • Francesco Di Virgilio, University of Ferrara
  • ,
  • Antonello Pileggi, Miami University
  • ,
  • Sirano Dhe-Paganon, Dana Farber Cancer Institute
  • ,
  • Gian Vincenzo Zuccotti, Luigi Sacco Hospital
  • ,
  • Paolo Fiorina, Boston Children's Hospital, Luigi Sacco Hospital, ASST Fatebenefratelli-Sacco

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.

OriginalsprogEngelsk
TidsskriftDiabetes
Vol/bind67
Nummer10
Sider (fra-til)2038-2053
Antal sider16
ISSN0012-1797
DOI
StatusUdgivet - 1 okt. 2018

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