Extracellular nicotinamide adenine dinucleotide induces T cell apoptosis in vivo and in vitro

Incubation of mouse T cells expressing the cell surface enzyme ADP ribosylt ransferase with nicotinamide adenine dinucleotide (NAD) had been reported t o cause ADP ribosylation of cell surface molecules, inhibition of transmemb rane signaling, and suppression of immune responses. In this study, we anal yze the reasons for these effects and report that contact of T cells with N AD causes cell death. Naive T cells when incubated with NAD and adoptively transferred into semiallogeneic mice fail to cause graft-vs-host disease, a nd when injected into syngeneic, T cell-deficient recipients do not reconst itute these mice. Rather, they accumulate in the liver, leading to an incre ase of apoptotic lymphocytes in this organ. Similar effects are induced by injection of NAD, shown to cause a dramatic increase of apoptotic CD3(+), C D4(+), and CD8(+) cells in the liver. Consistent with this, in vitro incuba tion of naive T cells with NAD is shown to induce apoptosis. In contrast, n o cell death is demonstrable when T cells are activated before incubation w ith NAD. It is concluded that ecto-NAD, as substrate of ADP ribosyltransfer ase, acts on naive, but not on activated CD69(+) T cells.