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NAD⁺ Released during Inflammation Participates in T Cell Homeostasis by Inducing ART2-Mediated Death of Naive T Cells In Vivo¹

Sahil Adriouch^*,,, Sandra Hubert^*,, Severine Pechberty^*, Friedrich Koch-Nolte^,, Friedrich Haag^, and Michel Seman^2,*,

^* University Denis Diderot-Paris 7, EA1556, Paris, France; Institut National de la Santé et de la Recherche Médicale Unité 519, Faculty of Medicine and Pharmacy, Rouen, France; Institute of Immunology, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Ligue Nationale Contre le Cancer, the Association pour la Recherche sur le Cancer, and the Ministère de la Recherche (to M.S.); the Fondation pour la Recherche Médicale (to S.A.), and the Deutsche Forschungsgemeinschaft (to F.K.-N. and F.H.).

² Address correspondence and reprint requests to Prof. Michel Seman, Institut National de la Santé et de la Recherche Médicale, U519, Rouen, F-76000, France. E-mail address: michel.seman{at}univ-rouen.fr

³ Abbreviations used in this paper: ART, ADP-ribosyltransferase; PI, propidium iodide; NADase, NAD⁺ glycohydrolase; ADH, alcohol dehydrogenase; PES, phenazyne ethosulfate; PS, phosphatidylserine; NICD, NAD⁺-induced T cell death.

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