Extracellular NAD+ shapes the Foxp3+ regulatory T cell compartment through the ART2-P2X7 pathway.
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.
Institut National de la Santé et de la Recherche Medicale, U905, 76183 Rouen, France.
Sandra
S
Hubert
Björn
B
Rissiek
Katjana
K
Klages
Jochen
J
Huehn
Tim
T
Sparwasser
Friedrich
F
Haag
Friedrich
F
Koch-Nolte
Olivier
O
Boyer
Michel
M
Seman
Sahil
S
Adriouch
D036002:ADP Ribose Transferases / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D051858:Forkhead Transcription Factors / Q000032:analysis*; D019041:L-Selectin / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009243:NAD / Q000032:analysis / Q000502:physiology*; D010718:Phosphatidylserines / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000502:physiology*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D010718:Phosphatidylserines; D058486:Receptors, Purinergic P2X7; D009243:NAD; D019041:L-Selectin; D036002:ADP Ribose Transferases; C449339:Art2b protein, mouse