P2X7 on Mouse T Cells: One Channel, Many Functions

International audience; The P2X7 receptor is an adenosine triphosphate (ATP)-gated cation channel that is expressed by several cells of the immune system. P2X7 is best known for its proinflamma-tory role in promoting inflammasome formation and release of mature interleukin (IL)-1β by innate immune cells. Mounting evidence indicates that P2X7 is also an important regulatory receptor of murine and human T cell functions. Murine T cells express a sensitive splice variant of P2X7 that can be activated either by non-covalent binding of ATP or, in the presence of nicotinamide adenine dinucleotide, by its covalent ADP-ribosylation catalyzed by the ecto-ADP-ribosyltransferase ARTC2.2. Prolonged activation of P2X7 by either one of these pathways triggers the induction of T cell death. Conversely, lower concentrations of ATP can activate P2X7 to enhance T cell proliferation and production of IL-2. In this review, we will highlight the molecular and cellular consequences of P2X7 activation on mouse T cells and its versatile role in T cell homeostasis and activation. Further, we will discuss important differences in the function of P2X7 on human and murine T cells. Mechanisms Leading to Activation of P2X7 by Extracellular ATP or NAD + on Mouse T Cells The family of ionotropic P2X receptors comprises seven members that are able to form trimeric ion channels reactive to extracellular adenosine triphosphate (ATP). In the context of the immune system, P2X7 is best known for its role in promoting inflammasome formation and release of the proinflammatory interleukin 1β (IL-1β) from innate immune cells such as macrophages and monocytes after exposure to lipopolysaccharide and ATP (1). Further, P2X7 has also been identified as an important regulator of mouse T cell functions. P2X7 triggered by extracellular ATP induces the formation of a non-selective cation channel, resulting in the influx of calcium and sodium ions as well as the efflux of potassium. Interestingly, P2X7 can also be triggered via an ATP-independent pathway that has been discovered and characterized on mouse T cells. The mechanism involves the ecto-ADP-ribosyltransferase ARTC2.2 which, in the presence of its substrate nicotinamide adenine dinucleotide (NAD +), catalyzes the ARTC2.2-dependent ADP-ribosylation of P2X7 at an arginine residue at position 125 at the edge of the ATP-binding pocket in the extracellular domain of the protein (Figure 1A) (2, 3). This covalent posttranslational modification occurs even at 4°C, however gating of P2X7 is triggered only at 37°C. Since NAD + is released during cell preparation, alterations of T cell phenotype and function due to NAD +-dependent ADP-ribosylation of P2X7 can easily be evidenced on freshly harvested T cells extracted from lymphoid organs following their re-incubation