Extracellular NAD+ shapes the Foxp3+ regulatory T cell compartment through the ART2-P2X7 pathway.
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Extracellular NAD+ shapes the Foxp3+ regulatory T cell compartment through the ART2-P2X7 pathway. / Hubert, Sandra; Rissiek, Björn; Klages, Katjana; Huehn, Jochen; Sparwasser, Tim; Haag, Friedrich; Koch Nolte, Friedrich; Boyer, Olivier; Seman, Michel; Adriouch, Sahil.
In: J EXP MED, Vol. 207, No. 12, 12, 2010, p. 2561-2568.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Extracellular NAD+ shapes the Foxp3+ regulatory T cell compartment through the ART2-P2X7 pathway.
AU - Hubert, Sandra
AU - Rissiek, Björn
AU - Klages, Katjana
AU - Huehn, Jochen
AU - Sparwasser, Tim
AU - Haag, Friedrich
AU - Koch Nolte, Friedrich
AU - Boyer, Olivier
AU - Seman, Michel
AU - Adriouch, Sahil
PY - 2010
Y1 - 2010
N2 - 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.
AB - 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.
M3 - SCORING: Zeitschriftenaufsatz
VL - 207
SP - 2561
EP - 2568
JO - J EXP MED
JF - J EXP MED
SN - 0022-1007
IS - 12
M1 - 12
ER -
