T Cells of Different Developmental Stages Differ in Sensitivity to Apoptosis Induced by Extracellular NAD

Abstract

Extracellular nucleotides such as ATP and NAD can profoundly affect the functions of lymphocytes, macrophages, and other cells. We have recently shown that extracellular NAD induces rapid apoptosis in naive T cells by a mechanism involving the ADP-ribosylation of cell surface molecules. In the present paper, we describe that T cells of different developmental stages differ in their sensitivity to NAD-induced apoptosis. Thymocytes were less susceptible than peripheral lymph node T cells, and freshly activated cells were more resistant than resting cells. Sensitivity to NAD-induced apoptosis generally correlated with expression of the ADP-ribosyltransferase ART2.2, which is not expressed on thymocytes and shed from peripheral T cells upon activation. Our findings suggest that NAD-induced apoptosis does not play a role during thymic selection of T cells, but rather may play a role by preventing the activation of unwanted bystander T cells during an immune response, and thus may participate in the control of autoimmunity.

NAD+ Released during Inflammation Participates in T Cell Homeostasis by Inducing ART2-Mediated Death of Naive T Cells In Vivo

“…In our experiments, the depletion is aggravated particularly in CD38 Ϫ/Ϫ mice where it affects Ͼ80% of the T cell population in peripheral lymphoid tissues. No effect of treatment on the thymus was observed (data not shown), in agreement with the absence of ART2 on thymocytes (38). The high sensitivity of CD38 Ϫ/Ϫ vs wild-type BALB/c mice to the deleterious effect of NAD ϩ is consistent with our previous observation indicating that the CD38 NADase, mainly expressed on B lymphocytes, controls the level of ART2-mediated ADP-ribosylation of T cell surface proteins and, therefore, T cell apoptosis in unfractionated peripheral lymphoid populations (28).…”

“…Three arguments support this conclusion. First, T cell activation leads to the shedding of ART2 by the TACE metalloproteinase and renders cells resistant to NICD (37,38). Evidently, most of the CD4 ϩ and CD8…”

Nuclear ADP-Ribosylation Reactions in Mammalian Cells: Where Are We Today and Where Are We Going?

“…However, only the roles of plasma membrane-associated cytosolic and ecto-ADP-ribosylation reactions (mono-ADP-ribosylation activities and ADPribose-cyclase activities) in cellular differentiation and proliferation processes (mainly in the immune system) have been analyzed on a functional level to date (150,194,286,295,388,406). The roles of nuclear ADP-ribosylation reactions (monoand poly-ADP-ribosylation) in these processes have yet to be investigated.…”

NAD+-Consuming Enzymes in the Regulation of Lung Immune Responses

“…Indeed, P2X7 in mouse T cells can be directly activated by ART2.2-mediated ADP-ribosylation, which induces calcium flux, pore formation, phosphatidylserine exposure, shedding of CD62L, cell shrinkage, and propidium iodide uptake [6]. Recently it has been shown that T cell activation induces down modulation of P2X7 expression and shedding of ART2 by TACE metalloproteinase leading to resistance to NICD [4,7,38]. Alternatively, CD4+Foxp3+ regulatory cells were demonstrated to be highly sensitive to NICD through the ART2-P2X7 pathway [8,39].…”

“…It has been demonstrated by Seman et al [6] that NAD+ selectively induces apoptosis of mouse T cells (both CD4+ and CD8+) but not B cells. Furthermore, the sensitivity to NICD is dependent on the developmental stage of lymphocytes [7]. Primed T cells escape the deleterious effect of NAD+, as fraction of activated/memory cells (CD44high, CD62Llow) is strongly enlarged after NAD+ treatment [4].…”