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      P2X7 receptor-dependent and -independent T cell death is induced by nicotinamide adenine dinucleotide.

      The Journal of Immunology Author Choice

      Time Factors, physiology, Adenosine Diphosphate Ribose, pharmacology, Animals, Apoptosis, immunology, Cell Death, drug effects, Cell Proliferation, Cells, Cultured, Female, Growth Inhibitors, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred NOD, ADP Ribose Transferases, Mice, Knockout, NAD, analogs & derivatives, metabolism, Receptors, Purinergic P2, deficiency, genetics, Receptors, Purinergic P2X7, Signal Transduction, Substrate Specificity, T-Lymphocytes, cytology, enzymology

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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 microM) 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 microM), 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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