Nicotinamide adenine dinucleotide (NAD) and its metabolites inhibit T lymphocyte proliferation: role of cell surface NAD glycohydrolase and pyrophosphatase activities
Biochemistry & Molecular Pharmacology
Graduate School of Biomedical Sciences; Department of Medicine, Diabetes Division; Department of Medicine, Division of Endocrinology and Metabolism
Medical Subject Headings
*ADP Ribose Transferases; Adenosine; Adenosine Diphosphate; Adenosine Diphosphate Ribose; Adenosine Monophosphate; Animals; Antigens, Differentiation, T-Lymphocyte; Cell Membrane; Cells, Cultured; Cholera Toxin; Female; Histocompatibility Antigens; Immunosuppressive Agents; *Lymphocyte Activation; Male; *Membrane Glycoproteins; Mitogens; NAD; NAD+ Nucleosidase; Pertussis Toxin; Phosphatidylinositol Diacylglycerol-Lyase; Phosphoinositide Phospholipase C; Phosphorus Radioisotopes; Poly(ADP-ribose) Polymerases; Pyrophosphatases; Rats; Rats, Inbred BB; Rats, Inbred WF; T-Lymphocytes; Type C Phospholipases; Virulence Factors, Bordetella
Life Sciences | Medicine and Health Sciences
The presence of NAD-metabolizing enzymes (e.g., ADP-ribosyltransferase (ART)2) on the surface of immune cells suggests a potential immunomodulatory activity for ecto-NAD or its metabolites at sites of inflammation and cell lysis where extracellular levels of NAD may be high. In vitro, NAD inhibits mitogen-stimulated rat T cell proliferation. To investigate the mechanism of inhibition, the effects of NAD and its metabolites on T cell proliferation were studied using ART2a+ and ART2b+ rat T cells. NAD and ADP-ribose, but not nicotinamide, inhibited proliferation of mitogen-activated T cells independent of ART2 allele-specific expression. Inhibition by P2 purinergic receptor agonists was comparable to that induced by NAD and ADP-ribose; these compounds were more potent than P1 agonists. Analysis of the NAD-metabolizing activity of intact rat T cells demonstrated that ADP-ribose was the predominant metabolite, consistent with the presence of cell surface NAD glycohydrolase (NADase) activities. Treatment of T cells with phosphatidylinositol-specific phospholipase C removed much of the NADase activity, consistent with at least one NADase having a GPI anchor; ART2- T cell subsets contained NADase activity that was not releasable by phosphatidylinositol-specific phospholipase C treatment. Formation of AMP from NAD and ADP-ribose also occurred, a result of cell surface pyrophosphatase activity. Because AMP and its metabolite, adenosine, were less inhibitory to rat T cell proliferation than was NAD or ADP-ribose, pyrophosphatases may serve a regulatory role in modifying the inhibitory effect of ecto-NAD on T cell activation. These data suggest that T cells express multiple NAD and adenine nucleotide-metabolizing activities that together modulate immune function.
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Citation: J Immunol. 2001 Aug 15;167(4):2049-59.