In:
Journal of Experimental Medicine, Rockefeller University Press, Vol. 207, No. 12 ( 2010-11-22), p. 2561-2568
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.
Type of Medium:
Online Resource
ISSN:
1540-9538
,
0022-1007
DOI:
10.1084/jem.20091154
Language:
English
Publisher:
Rockefeller University Press
Publication Date:
2010
detail.hit.zdb_id:
218343-2
detail.hit.zdb_id:
1477240-1
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