During a study aiming at the identification of genes selectively expressed by immune cells, our laboratory has identified over a
decade ago the gene coding for a nicotinamidephosphoribosyltransferase (Nampt), an enzyme involved in NAD biosynthesis. Of
interest, expression of this gene was found upregulated following antigen stimulation of both innate and adaptive cells. These
observations, independently confirmed by others, led us to further explore the possible relationship between NAD metabolism and the control
of immune responses. Nicotinamide adenine dinucleotide (NAD) has been known for several decades to play a major role as a coenzyme
in numerous oxidation-reduction reactions. Recently however, the distinct role of NAD as a precursor for molecules involved in
regulatory processes has also been recognized. Numerous enzymesinvolved in post-translational modification of target proteins and
using NAD as a substrate have been identified in mammals and include mono and poly (ADP-ribosyl) transferases (respectively mARTs and
PARPs) and deacylases such as Sirtuins. This later family comprises seven members (SIRT1 to SIRT7), whosedeacylase activity
appears as strictly linked to intracellular NAD levels. Though the modulation of intracellular NAD levels, Nampt appears therefore to
play an important role in the regulation of sirtuin activity. Notably, sirtuins have recently attracted great interest following
the demonstration that they may play a role in cell longevity and responses to stress. Based on these considerations, we have
undertaken a series of research projects to evaluate the role of the Nampt-NAD-sirtuin axis in the regulation of an immune response.
These studies have led to the discovery of the important role of Nampt in lymphocyte development and in the control of TNF (an
important pro-inflammatory factor) secretion. Our current studies aim at identifying the role of sirtuins in other aspects of immune
regulation including T lymphocyte activation and differentiation.