Islet-derived EATP fuels autoreactive CD8+ T cells and facilitates the onset of type 1 diabetes

Sara Tezza; Moufida Ben Nasr; Francesca D'Addio; Andrea Vergani; Vera Usuelli; Simonetta Falzoni; Roberto Bassi; Sergio Dellepiane; Carmen Fotino; Chiara Rossi; Anna Maestroni; Anna Solini; Domenico Corradi; Elisa Giani; Chiara Mameli; Federico Bertuzzi; Marcus G. Pezzolesi; Clive H. Wasserfall; Mark A. Atkinson; Ernst Martin Füchtbauer; Camillo Ricordi; Franco Folli; Francesco Di Virgilio; Antonello Pileggi; Sirano Dhe-Paganon; Gian Vincenzo Zuccotti; Paolo Fiorina

doi:10.2337/db17-1227

Islet-derived EATP fuels autoreactive CD8⁺ T cells and facilitates the onset of type 1 diabetes

Sara Tezza, Moufida Ben Nasr, Francesca D'Addio, Andrea Vergani, Vera Usuelli, Simonetta Falzoni, Roberto Bassi, Sergio Dellepiane, Carmen Fotino, Chiara Rossi, Anna Maestroni, Anna Solini, Domenico Corradi, Elisa Giani, Chiara Mameli, Federico Bertuzzi, Marcus G. Pezzolesi, Clive H. Wasserfall, Mark A. Atkinson, Ernst Martin FüchtbauerCamillo Ricordi, Franco Folli, Francesco Di Virgilio, Antonello Pileggi, Sirano Dhe-Paganon, Gian Vincenzo Zuccotti, Paolo Fiorina

Surgery

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

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.

Original language	English (US)
Pages (from-to)	2038-2053
Number of pages	16
Journal	Diabetes
Volume	67
Issue number	10
DOIs	https://doi.org/10.2337/db17-1227
State	Published - Oct 2018

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism

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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., ... Fiorina, P. (2018). Islet-derived EATP fuels autoreactive CD8⁺ T cells and facilitates the onset of type 1 diabetes. Diabetes, 67(10), 2038-2053. https://doi.org/10.2337/db17-1227

Islet-derived EATP fuels autoreactive CD8⁺ T cells and facilitates the onset of type 1 diabetes. / Tezza, Sara; Nasr, Moufida Ben; D'Addio, Francesca; Vergani, Andrea; Usuelli, Vera; Falzoni, Simonetta; Bassi, Roberto; Dellepiane, Sergio; Fotino, Carmen; Rossi, Chiara; Maestroni, Anna; Solini, Anna; Corradi, Domenico; Giani, Elisa; Mameli, Chiara; Bertuzzi, Federico; Pezzolesi, Marcus G.; Wasserfall, Clive H.; Atkinson, Mark A.; Füchtbauer, Ernst Martin; Ricordi, Camillo; Folli, Franco; Virgilio, Francesco Di; Pileggi, Antonello; Dhe-Paganon, Sirano; Zuccotti, Gian Vincenzo; Fiorina, Paolo.

In: Diabetes, Vol. 67, No. 10, 10.2018, p. 2038-2053.

Research output: Contribution to journal › Article › peer-review

Tezza, S, Nasr, MB, 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, Ricordi, C, Folli, F, Virgilio, FD, Pileggi, A, Dhe-Paganon, S, Zuccotti, GV & Fiorina, P 2018, 'Islet-derived EATP fuels autoreactive CD8⁺ T cells and facilitates the onset of type 1 diabetes', Diabetes, vol. 67, no. 10, pp. 2038-2053. https://doi.org/10.2337/db17-1227

Tezza, Sara ; Nasr, Moufida Ben ; D'Addio, Francesca ; Vergani, Andrea ; Usuelli, Vera ; Falzoni, Simonetta ; Bassi, Roberto ; Dellepiane, Sergio ; Fotino, Carmen ; Rossi, Chiara ; Maestroni, Anna ; Solini, Anna ; Corradi, Domenico ; Giani, Elisa ; Mameli, Chiara ; Bertuzzi, Federico ; Pezzolesi, Marcus G. ; Wasserfall, Clive H. ; Atkinson, Mark A. ; Füchtbauer, Ernst Martin ; Ricordi, Camillo ; Folli, Franco ; Virgilio, Francesco Di ; Pileggi, Antonello ; Dhe-Paganon, Sirano ; Zuccotti, Gian Vincenzo ; Fiorina, Paolo. / Islet-derived EATP fuels autoreactive CD8⁺ T cells and facilitates the onset of type 1 diabetes. In: Diabetes. 2018 ; Vol. 67, No. 10. pp. 2038-2053.

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title = "Islet-derived EATP fuels autoreactive CD8+ T cells and facilitates the onset of type 1 diabetes",

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.",

author = "Sara Tezza and Nasr, {Moufida Ben} and Francesca D'Addio and Andrea Vergani and Vera Usuelli and Simonetta Falzoni and Roberto Bassi and Sergio Dellepiane and Carmen Fotino and Chiara Rossi and Anna Maestroni and Anna Solini and Domenico Corradi and Elisa Giani and Chiara Mameli and Federico Bertuzzi and Pezzolesi, {Marcus G.} and Wasserfall, {Clive H.} and Atkinson, {Mark A.} and F{\"u}chtbauer, {Ernst Martin} and Camillo Ricordi and Franco Folli and Virgilio, {Francesco Di} and Antonello Pileggi and Sirano Dhe-Paganon and Zuccotti, {Gian Vincenzo} and Paolo Fiorina",

note = "Publisher Copyright: {\textcopyright} 2018 by the American Diabetes Association.",

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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

PY - 2018/10

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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.

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