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.
journal_name
Diabetesjournal_title
Diabetesauthors
Tezza S,Ben Nasr M,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 MG,Wasserfall CH,Atkinson MA,Füchtbauer EM,Ricodoi
10.2337/db17-1227subject
Has Abstractpub_date
2018-10-01 00:00:00pages
2038-2053issue
10eissn
0012-1797issn
1939-327Xpii
db17-1227journal_volume
67pub_type
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