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

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

Journal article

Open access

Peer reviewed

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, …

Diabetes (New York, N.Y.), Vol.67(10), pp.2038-2053

2018-10

DOI: https://doi.org/10.2337/db17-1227

PMCID: PMC6905486

PMID: 30065030

Abstract

Humans

Autoimmunity - genetics

Diabetes Mellitus, Type 1 - genetics

Diabetes Mellitus, Type 1 - metabolism

Mutation - genetics

Adenosine Triphosphate - analogs & derivatives

Receptors, Purinergic P2X7 - genetics

Adenosine Triphosphate - pharmacology

Autoimmunity - physiology

Animals

Flow Cytometry

Lymphocyte Activation - drug effects

Adenosine Triphosphate - metabolism

CD8-Positive T-Lymphocytes - metabolism

Receptors, Purinergic P2X7 - metabolism

Female

Mice, Inbred NOD

Mice

Mice, Inbred BALB C

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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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.159 Membrane Channels & Receptors; 1.159.576 Adenosine
Web Of Science research areas: Endocrinology & Metabolism
ESI research areas: Clinical Medicine

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Title: Islet-Derived eATP Fuels Autoreactive CD8 + T Cells and Facilitates the Onset of Type 1 Diabetes
Creators: Sara Tezza - Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA
Moufida Ben Nasr - International Center for Type 1 Diabetes, Pediatric Clinical Romeo and Enrica Invernizzi Research Center, and L. Sacco Department of Biomedical and Clinical Science, University of Milan, Milan, Italy
Francesca D'Addio - International Center for Type 1 Diabetes, Pediatric Clinical Romeo and Enrica Invernizzi Research Center, and L. Sacco Department of Biomedical and Clinical Science, University of Milan, Milan, Italy
Andrea Vergani - Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA
Vera Usuelli - International Center for Type 1 Diabetes, Pediatric Clinical Romeo and Enrica Invernizzi Research Center, and L. Sacco Department of Biomedical and Clinical Science, University of Milan, Milan, Italy
Simonetta Falzoni - Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
Roberto Bassi - Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA
Sergio Dellepiane - Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA
Carmen Fotino - Diabetes Research Institute, University of Miami, FL
Chiara Rossi - Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
Anna Maestroni - International Center for Type 1 Diabetes, Pediatric Clinical Romeo and Enrica Invernizzi Research Center, and L. Sacco Department of Biomedical and Clinical Science, University of Milan, Milan, Italy
Anna Solini - Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy
Domenico Corradi - Pathology and Laboratory Medicine, University of Parma, Parma, Italy
Elisa Giani - Pediatric Clinical Romeo and Enrica Invernizzi Research Center, L. Sacco Department of Biomedical and Clinical Science, University of Milan, and Department of Pediatrics, Children's Hospital Buzzi, Milan, Italy
Chiara Mameli - Pediatric Clinical Romeo and Enrica Invernizzi Research Center, L. Sacco Department of Biomedical and Clinical Science, University of Milan, and Department of Pediatrics, Children's Hospital Buzzi, Milan, Italy
Federico Bertuzzi - Diabetology Unit, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
Marcus G Pezzolesi - Division of Nephrology & Hypertension and Diabetes & Metabolism Research Center, University of Utah, Salt Lake City, UT
Clive H Wasserfall - Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL
Mark A Atkinson - Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL
Ernst-Martin Füchtbauer - Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
Camillo Ricordi - Diabetes Research Institute, University of Miami, FL
Franco Folli - ASST Santi Paolo e Carlo, Ospedali San Paolo e San Carlo Borromeo, Milan, Italy
Francesco Di Virgilio - Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
Antonello Pileggi - Diabetes Research Institute, University of Miami, FL
Sirano Dhe-Paganon - Structural Biology Center, Dana-Farber Cancer Institute, Boston, MA
Gian Vincenzo Zuccotti - Pediatric Clinical Romeo and Enrica Invernizzi Research Center, L. Sacco Department of Biomedical and Clinical Science, University of Milan, and Department of Pediatrics, Children's Hospital Buzzi, Milan, Italy
Paolo Fiorina - Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
Publication Details: Diabetes (New York, N.Y.), Vol.67(10), pp.2038-2053
Publisher: United States
Grant note: P01 AI042288 / NIAID NIH HHS
Academic Unit: Leadership Department; Miller School of Medicine; Diabetes Research Institute (DRI)
Language: English
Resource Type: Journal article
PMID: 30065030
PMCID: PMC6905486
Record Identifier: 991031578339402976