NAD+ released during inflammation participates in T cell homeostasis by inducing ART2-mediated death of naive T cells in vivo.
Mono ADP-ribosyltransferase 2 (ART2) is an ectoenzyme expressed on mouse T lymphocytes, which catalyze the transfer of ADP-ribose groups from NAD(+) onto several target proteins. In vitro, ADP-ribosylation by ART2 activates the P2X7 ATP receptor and is responsible for NAD(+)-induced T cell death (NICD). Yet, the origin of extracellular NAD(+) and the role of NICD in vivo remain elusive. In a model of acute inflammation induced by polyacrylamide beads, we demonstrate release of NAD(+) into exudates during the early phase of the inflammatory response. This leads to T cell depletion in the draining lymph nodes from wild-type and, more severely, from mice lacking the CD38 NAD(+) glycohydrolase, whereas no effect is observed in ART2-deficient animals. Intravenous injection of NAD(+) used to exacerbate NICD in vivo results in fast and dramatic ART2- and P2X7-dependent depletion of CD4+ and CD8+ T lymphocytes, which can affect up to 80% of peripheral T cells in CD38(-/-) mice. This affects mainly naive T cells as most cells surviving in vivo NAD+ treatment exhibit the phenotype of recently activated/memory cells. Consistently, treatment with NAD(+) abolishes primary Ab response to a T-dependent Ag in NICD-susceptible CD38(-/-) mice but has no effect on the secondary response when given several days after priming. Unexpectedly NAD+ treatment improves the response in their wild-type BALB/c counterparts. We propose that NAD(+) released during early inflammation facilitates the expansion of primed T cells, through ART2-driven death of resting cells, thus contributing to the dynamic regulation of T cell homeostasis.
Adriouch
Sahil
S
University Denis Diderot-Paris 7, EA 1556 Paris, France.
Hubert
Sandra
S
Pechberty
Severine
S
Koch-Nolte
Friedrich
F
Haag
Friedrich
F
Seman
Michel
M
D036002:ADP Ribose Transferases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D016923:Cell Death / Q000276:immunology; D006706:Homeostasis / Q000235:genetics / Q000276:immunology*; D007156:Immunologic Memory; D016130:Immunophenotyping; D018836:Inflammation Mediators / Q000378:metabolism* / Q000502:physiology; D007275:Injections, Intravenous; D008213:Lymphocyte Activation / Q000276:immunology; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009243:NAD / Q000008:administration & dosage / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D010084:Oxidation-Reduction; D016192:Resting Phase, Cell Cycle / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*
D018836:Inflammation Mediators; D009243:NAD; D036002:ADP Ribose Transferases; C449322:Art2a protein, mouse; C449339:Art2b protein, mouse