Extracellular Nicotinamide Adenine Dinucleotide Induces T Cell Apoptosis In Vivo and In Vitro

Liu, Zhang–Xu; Azhipa, Olga; Okamoto, Shigefumi; Govindarajan, Sugantha; Dennert, Günther

doi:10.4049/jimmunol.167.9.4942

Cited by 41 publications

(46 citation statements)

References 35 publications

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“…Treating naive T cells with NAD before injection into semiallogeneic mice blocks induction of graft-vs-host disease (2). Treating T cells before injection into syngeneic mice blocks their migration to the spleen and directs them to the liver where they appear to die (2).…”

Section: T He Addition Of Nad To Murine T Lymphocytes Inhibits Their mentioning

confidence: 99%

P2X7 Receptor-Dependent and -Independent T Cell Death Is Induced by Nicotinamide Adenine Dinucleotide

Kawamura

Aswad

Minagawa

et al. 2005

The Journal of Immunology

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Adding NAD to murine T lymphocytes inhibits their functions and induces annexin V binding. This report shows that NAD induces cell death in a subset of T cells within seconds whereas others do not die until many hours later. Low NAD concentrations (<10 μM) suffice to trigger rapid cell death, which is associated with annexin V binding and membrane pore formation, is not blocked by the caspase inhibitor Z-VADfmk, and requires functional P2X7 receptors. The slower induction of death requires higher NAD concentrations (>100 μM), is blocked by caspase inhibitor Z-VADfmk, is associated with DNA fragmentation, and does not require P2X7 receptors. T cells degrade NAD to ADP-ribose (ADPR), and adding ADPR to T cells leads to slow but not rapid cell death. NAD but not ADPR provides the substrate for ADP-ribosyltransferase (ART-2)-mediated attachment of ADP-ribosyl groups to cell surface proteins; expression of ART-2 is required for NAD to trigger rapid but not slow cell death. These results support the hypothesis that cell surface ART-2 uses NAD but not ADPR to attach ADP-ribosyl groups to the cell surface, and that these groups act as ligands for P2X7 receptors that then induce rapid cell death. Adding either NAD or ADPR also triggers a different set of mechanisms, not requiring ART-2 or P2X7 receptors that more slowly induce cell death.

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Section: T He Addition Of Nad To Murine T Lymphocytes Inhibits Their mentioning

confidence: 99%

P2X7 Receptor-Dependent and -Independent T Cell Death Is Induced by Nicotinamide Adenine Dinucleotide

Kawamura

Aswad

Minagawa

et al. 2005

The Journal of Immunology

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“…ART2-mediated modification of surface proteins would thus have an inhibitory effect on the expansion of T cell responses. As previously mentioned, NAD+ was shown to induce T cell apoptosis [5]. This was demonstrated to be an ART2-dependent mechanism [33,36].…”

Section: Art2mentioning

confidence: 74%

“…Recently it has been shown that a significant level of NAD+ is present in exudates during the early phase of the inflammatory response and that this concentration is sufficient to provoke NAD+-induced T cell death (NICD) in vitro [4]. Injection of NAD+ into wild type mice induces massive depletion of T cells [4,5] confirming the inhibitory function of NAD+ in T cell proliferation and cytotoxic activity in vitro [5]. It has been demonstrated by Seman et al [6] that NAD+ selectively induces apoptosis of mouse T cells (both CD4+ and CD8+) but not B cells.…”

Section: Introductionmentioning

confidence: 99%

NAD+-Consuming Enzymes in the Regulation of Lung Immune Responses

Legutko¹,

Lekeux²,

Bureau³

2009

TOIJ

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Nicotinamide adenine dinucleotide (NAD+) plays a role as a coenzyme in numerous oxidation-reduction reactions and mediates not only energy metabolism and mitochondrial functions, but also calcium homeostasis, aging, and cell death. Moreover, extensive evidence attests to the great importance of the non-redox functions of NAD+ via NAD+-consuming enzymes. Indeed, ADP-ribose transferases, cADP-ribose synthases and sirtuins emerge as NAD+ dependent enzymes with potent regulatory function in many physiological and pathophysiological processes. They have been shown to be involved in several neurological and cardiovascular disorders as well as in cancer and inflammation. In this review we will summarize the current knowledge about function of NAD+-consuming enzymes in the regulation of the immune system with particular emphasis on lung inflammatory disorders.

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“…Human monocytes basally express ART3 mRNA and inducibly express ART4 mRNA in response to LPS priming [35,36]; however, neither ART3 nor ART4 appear to act as functionally active ADPribosyltransferases. As noted previously, the expression and function of the ART2 gene products have been extensively characterized in murine T cells [9,17,33,37] and we recently reported that ART2.1 is selectively expressed in murine BMDM stimulated with IFNs or LPS [16]. These new data conclusively demonstrate that ART2.1 is expressed as a functional ecto-enzyme in a much broader range of leukocyte subtypes (dendritic cells, macrophages, B cells, and T cells) than is ART2.2 which appears restricted to T cell subsets.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, freshly isolated T cells from the same mice basally express both ART2.1 and ART2.2 [17][18][19][20][21][22][23]. Given these striking differences in expression of ART2.1 and ART2.2 in different leukocyte subsets and under in vivo versus in vitro conditions, this study was designed to address two major questions: (1) Is ART2.1 is expressed in leukocyte types other than macrophages and T cells?…”

Section: Introductionmentioning

confidence: 99%

Basal and inducible expression of the thiol-sensitive ART2.1 ecto-ADP-ribosyltransferase in myeloid and lymphoid leukocytes

Hong

Brass²,

Séman

et al. 2009

Purinergic Signalling

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ADP-ribosylation of cell surface proteins in mammalian cells is a post-translational modification by which ecto-ADP-ribosyltransferases (ARTs) transfer ADPribose from extracellular NAD to protein targets. The ART2 locus at murine chromosome 7 encompasses the tandem Art2a and Art2b genes that encode the distinct ART2.1 and ART2.2 proteins. Although both ecto-enzymes share 80% sequence identity, ART2.1 activity is uniquely regulated by an allosteric disulfide bond that is reducible in the presence of extracellular thiols, such as cysteine and glutathione, that accumulate in hypoxic and ischemic tissues. Previous studies have characterized the expression of ART2.1 and ART2.2 in murine T lymphocytes but not in other major classes of lymphoid and myeloid leukocytes. Here, we describe the expression of ART2.1 activity in a wide range of freshly isolated or tissue-cultured murine myeloid and lymphoid leukocytes. Spleen-derived macrophages, dendritic cells (DC), and B cells constitutively express ART2.1 as their predominant ART while spleen T cells express both ART2.1 and the thiol-independent ART2.2 isoform. Although bone-marrow-derived macrophages (BMDM) and dendritic cells (BMDC) constitutively express ART2.1 at low levels, it is markedly up-regulated when these cells are stimulated in vitro with IFNβ or IFNγ. ART2.1 expression and activity in splenic B cells is modestly up-regulated during incubation in vitro for 24 h, a condition that promotes B cell apoptosis. This increase in ART2.1 is attenuated by IL-4 (a B cell survival factor), but is not affected by IFNβ/γ, suggesting a possible induction of ART2.1 as an ancillary response to B cell apoptosis. In contrast, ART2.1 and ART2.2, which are highly expressed in freshly isolated splenic T cells, are markedly downregulated when purified T cells are incubated in vitro for 12-24 h. Studies with the BW5147 mouse thymocyte line verified basal expression of ART2.1 and ART2.2, as in primary spleen T cells, and demonstrated that both isoforms can be up-regulated when T cells are maintained in the presence of IFNs. Comparison of the surface proteins which are ADP-ribosylated by ART2.1 in the different leukocyte subtypes indicated both shared and cell-specific proteins as ART2.1 substrates. The LFA-1 integrin, a major target for ART2.2 in T cells, is also ADP-ribosylated by the ART2.1 expressed in macrophages. Thus, ART2.1, in contrast to ART2.2, is expressed in a broad range of myeloid and lymphoid leukocytes. The thiol redox-sensitive nature of this ecto-enzyme suggests an involvement in purinergic signaling that occurs in the combined context of inflammation and hypoxia/ischemia.

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Extracellular Nicotinamide Adenine Dinucleotide Induces T Cell Apoptosis In Vivo and In Vitro

Cited by 41 publications

References 35 publications

P2X7 Receptor-Dependent and -Independent T Cell Death Is Induced by Nicotinamide Adenine Dinucleotide

P2X7 Receptor-Dependent and -Independent T Cell Death Is Induced by Nicotinamide Adenine Dinucleotide

NAD+-Consuming Enzymes in the Regulation of Lung Immune Responses

Basal and inducible expression of the thiol-sensitive ART2.1 ecto-ADP-ribosyltransferase in myeloid and lymphoid leukocytes

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