Extracellular nicotinamide adenine dinucleotide induces t cell apoptosis in vivo and in vitro
1Department of Molecular Microbiology and Immunology, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine at University of Southern California, Los Angeles, CA 90089, USA.
Abstract:
Incubation of mouse T cells expressing the cell surface enzyme ADP ribosyltransferase with nicotinamide adenine dinucleotide (NAD) had been reported to cause ADP ribosylation of cell surface molecules, inhibition of transmembrane signaling, and suppression of immune responses. In this study, we analyze the reasons for these effects and report that contact of T cells with NAD causes cell death. Naive T cells when incubated with NAD and adoptively transferred into semiallogeneic mice fail to cause graft-vs-host disease, and when injected into syngeneic, T cell-deficient recipients do not reconstitute these mice. Rather, they accumulate in the liver, leading to an increase of apoptotic lymphocytes in this organ. Similar effects are induced by injection of NAD, shown to cause a dramatic increase of apoptotic CD3(+), CD4(+), and CD8(+) cells in the liver. Consistent with this, in vitro incubation of naive T cells with NAD is shown to induce apoptosis. In contrast, no cell death is demonstrable when T cells are activated before incubation with NAD. It is concluded that ecto-NAD, as substrate of ADP ribosyltransferase, acts on naive, but not on activated CD69(+) T cells.
Insights
Nicotinamide adenine dinucleotide (NAD) induces apoptosis in naive T cells, but not activated ones. This cell death mechanism in T cells may impact immune responses and transplantation outcomes.
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- T cells expressing ADP ribosyltransferase can be affected by nicotinamide adenine dinucleotide (NAD).
- Previous reports suggest NAD causes T cell molecule modification, signaling inhibition, and immune suppression.
Purpose of the Study:
- To investigate the mechanism by which NAD affects T cells.
- To determine if NAD induces T cell death and under what conditions.
Main Methods:
- In vitro incubation of naive and activated T cells with NAD.
- Adoptive transfer of NAD-treated T cells into semiallogeneic and syngeneic recipients.
- Analysis of T cell apoptosis in vivo and in vitro.
- Flow cytometry to identify apoptotic CD3(+), CD4(+), and CD8(+) cells.
Main Results:
- Incubation of naive T cells with NAD induces apoptosis.
- NAD administration leads to increased apoptotic lymphocytes, particularly CD3(+), CD4(+), and CD8(+) cells, in the liver.
- Activated T cells (CD69(+)) do not undergo cell death upon incubation with NAD.
- NAD-treated T cells failed to cause graft-vs-host disease or reconstitute T cell-deficient recipients.
Conclusions:
- Ecto-NAD acts as a substrate for ADP ribosyltransferase, selectively inducing apoptosis in naive T cells.
- Activated T cells are resistant to NAD-induced apoptosis.
- NAD-induced T cell death may explain previously observed immune suppression and affect transplantation success.
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