Nicotinamide adenine dinucleotide (NAD) and its metabolites inhibit T lymphocyte proliferation: role of cell surface NAD glycohydrolase and pyrophosphatase activities
McKenna, Robert C.
Rigby, Mark R.
Stevens, Linda A.
Patton, Walter A.
Mordes, John P.
Greiner, Dale L.
Rossini, Aldo A.
UMass Chan AffiliationsDepartment of Medicine, Division of Endocrinology and Metabolism
Department of Medicine, Diabetes Division
Graduate School of Biomedical Sciences
Keywords*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
Medicine and Health Sciences
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AbstractThe 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.
J Immunol. 2001 Aug 15;167(4):2049-59.
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/32545