Extracellular NAD+ shapes the Foxp3+ regulatory T cell compartment through the ART2-P2X7 pathway.

2.50
Hdl Handle:
http://hdl.handle.net/10033/132850
Title:
Extracellular NAD+ shapes the Foxp3+ regulatory T cell compartment through the ART2-P2X7 pathway.
Authors:
Hubert, Sandra; Rissiek, Björn; Klages, Katjana; Huehn, Jochen; Sparwasser, Tim; Haag, Friedrich; Koch-Nolte, Friedrich; Boyer, Olivier; Seman, Michel; Adriouch, Sahil
Abstract:
CD4(+)CD25(+)FoxP3(+) regulatory T cells (T reg cells) play a major role in the control of immune responses but the factors controlling their homeostasis and function remain poorly characterized. Nicotinamide adenine dinucleotide (NAD(+)) released during cell damage or inflammation results in ART2.2-mediated ADP-ribosylation of the cytolytic P2X7 receptor on T cells. We show that T reg cells express the ART2.2 enzyme and high levels of P2X7 and that T reg cells can be depleted by intravenous injection of NAD(+). Moreover, lower T reg cell numbers are found in mice deficient for the NAD-hydrolase CD38 than in wild-type, P2X7-deficient, or ART2-deficient mice, indicating a role for extracellular NAD(+) in T reg cell homeostasis. Even routine cell preparation leads to release of NAD(+) in sufficient quantities to profoundly affect T reg cell viability, phenotype, and function. We demonstrate that T reg cells can be protected from the deleterious effects of NAD(+) by an inhibitory ART2.2-specific single domain antibody. Furthermore, selective depletion of T reg cells by systemic administration of NAD(+) can be used to promote an antitumor response in several mouse tumor models. Collectively, our data demonstrate that NAD(+) influences survival, phenotype, and function of T reg cells and provide proof of principle that acting on the ART2-P2X7 pathway represents a new strategy to manipulate T reg cells in vivo.
Affiliation:
Institut National de la Santé et de la Recherche Medicale, U905, 76183 Rouen, France.
Citation:
Extracellular NAD+ shapes the Foxp3+ regulatory T cell compartment through the ART2-P2X7 pathway. 2010, 207 (12):2561-8 J. Exp. Med.
Journal:
The Journal of experimental medicine
Issue Date:
22-Nov-2010
URI:
http://hdl.handle.net/10033/132850
DOI:
10.1084/jem.20091154
PubMed ID:
20975043
Type:
Article
Language:
en
ISSN:
1540-9538
Appears in Collections:
publications of the division experimentelle Immunologie (EXIM)

Full metadata record

DC FieldValue Language
dc.contributor.authorHubert, Sandraen
dc.contributor.authorRissiek, Björnen
dc.contributor.authorKlages, Katjanaen
dc.contributor.authorHuehn, Jochenen
dc.contributor.authorSparwasser, Timen
dc.contributor.authorHaag, Friedrichen
dc.contributor.authorKoch-Nolte, Friedrichen
dc.contributor.authorBoyer, Olivieren
dc.contributor.authorSeman, Michelen
dc.contributor.authorAdriouch, Sahilen
dc.date.accessioned2011-06-09T10:50:03Z-
dc.date.available2011-06-09T10:50:03Z-
dc.date.issued2010-11-22-
dc.identifier.citationExtracellular NAD+ shapes the Foxp3+ regulatory T cell compartment through the ART2-P2X7 pathway. 2010, 207 (12):2561-8 J. Exp. Med.en
dc.identifier.issn1540-9538-
dc.identifier.pmid20975043-
dc.identifier.doi10.1084/jem.20091154-
dc.identifier.urihttp://hdl.handle.net/10033/132850-
dc.description.abstractCD4(+)CD25(+)FoxP3(+) regulatory T cells (T reg cells) play a major role in the control of immune responses but the factors controlling their homeostasis and function remain poorly characterized. Nicotinamide adenine dinucleotide (NAD(+)) released during cell damage or inflammation results in ART2.2-mediated ADP-ribosylation of the cytolytic P2X7 receptor on T cells. We show that T reg cells express the ART2.2 enzyme and high levels of P2X7 and that T reg cells can be depleted by intravenous injection of NAD(+). Moreover, lower T reg cell numbers are found in mice deficient for the NAD-hydrolase CD38 than in wild-type, P2X7-deficient, or ART2-deficient mice, indicating a role for extracellular NAD(+) in T reg cell homeostasis. Even routine cell preparation leads to release of NAD(+) in sufficient quantities to profoundly affect T reg cell viability, phenotype, and function. We demonstrate that T reg cells can be protected from the deleterious effects of NAD(+) by an inhibitory ART2.2-specific single domain antibody. Furthermore, selective depletion of T reg cells by systemic administration of NAD(+) can be used to promote an antitumor response in several mouse tumor models. Collectively, our data demonstrate that NAD(+) influences survival, phenotype, and function of T reg cells and provide proof of principle that acting on the ART2-P2X7 pathway represents a new strategy to manipulate T reg cells in vivo.en
dc.language.isoenen
dc.subject.meshADP Ribose Transferasesen
dc.subject.meshAnimalsen
dc.subject.meshApoptosisen
dc.subject.meshForkhead Transcription Factorsen
dc.subject.meshL-Selectinen
dc.subject.meshMiceen
dc.subject.meshMice, Inbred C57BLen
dc.subject.meshNADen
dc.subject.meshPhosphatidylserinesen
dc.subject.meshReceptors, Purinergic P2X7en
dc.subject.meshSignal Transductionen
dc.subject.meshT-Lymphocytes, Regulatoryen
dc.titleExtracellular NAD+ shapes the Foxp3+ regulatory T cell compartment through the ART2-P2X7 pathway.en
dc.typeArticleen
dc.contributor.departmentInstitut National de la Santé et de la Recherche Medicale, U905, 76183 Rouen, France.en
dc.identifier.journalThe Journal of experimental medicineen

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