P2X7 Receptor at the Crossroads of T Cell Fate

Abstract

The P2X7 receptor is a ligand-gated, cation-selective channel whose main physiological ligand is ATP. P2X7 receptor activation may also be triggered by ARTC2.2-dependent ADP ribosylation in the presence of extracellular NAD. Upon activation, this receptor induces several responses, including the influx of calcium and sodium ions, phosphatidylserine externalization, the formation of a non-selective membrane pore, and ultimately cell death. P2X7 receptor activation depends on the availability of extracellular nucleotides, whose concentrations are regulated by the action of extracellular nucleotidases such as CD39 and CD38. The P2X7 receptor has been extensively studied in the context of the immune response, and it has been reported to be involved in inflammasome activation, cytokine production, and the migration of different innate immune cells in response to ATP. In adaptive immune responses, the P2X7 receptor has been linked to T cell activation, differentiation, and apoptosis induction. In this review, we will discuss the evidence of the role of the P2X7 receptor on T cell differentiation and in the control of T cell responses in inflammatory conditions.

Role of P2X7 Receptors in Immune Responses During Neurodegeneration

“…As recently reviewed by Grassi (2020) and by Rivas-Yáñez et al (2020) , P2X7 receptors participate in T lymphocyte cell activation, migration, and differentiation. It interferes in lymph node traffic through CD62L shedding, thus being essential for CD4 + cell responses to injury ( Yip et al, 2009 ; Foster et al, 2013 ; Grassi, 2020 ; Rivas-Yáñez et al, 2020 ). In the brain, as observed in the mouse model of experimental autoimmune encephalomyelitis (EAE), Th1 cells could induce macrophage and microglia cell activation through secretion of IFN γ ( Murphy et al, 2010 ).…”

“…T helper CD4 + cells drive the immune response according to the pathogen (Korn and Kallies, 2017) and express both P2X7A and P2X7B receptors variants (Cheewatrakoolpong et al, 2005). As recently reviewed by Grassi (2020) and by Rivas-Yáñez et al (2020), P2X7 receptors participate in T lymphocyte cell activation, migration, and differentiation. It interferes in lymph node traffic through CD62L shedding, thus being essential for CD4 + cell responses to injury (Yip et al, 2009;Foster et al, 2013;Grassi, 2020;Rivas-Yáñez et al, 2020).…”

“…Additionally, P2X7 receptor activation induced the release of MMP-9 by peripheral blood mononuclear cells and in both purified monocyte and T-cell populations ( Gu and Wiley, 2006 ), indicating that immune cells may release factors that also contribute to BBB disruption, favoring brain invasion. Dendritic cells, responsible for activating T-cells by positioning them in the surface of cells in contact with pathogens, migrate and release interleukins and pro-inflammatory factors upon P2X7 receptor activation, determining T-cell polarization ( Rivas-Yáñez et al, 2020 ). Once in the brain, these factors could increase neuroinflammation, worsening brain injury in neurodegenerative diseases.…”

Pannexin Channel Regulation of Cell Migration: Focus on Immune Cells

“…Adaptive immune response progression requires purinergic signaling to modulate T cell functions ( 28 ). For example, P2X 7 receptor modulates the balance between the number of differentiated Th 17 and T reg lymphocytes ( 62 ). Accordingly, PANX1 and purinergic receptors are essential for T cell activation and cell death ( 63 – 65 ).…”

Special Issue of International Journal of Molecular Sciences (IJMS) “Purinergic P2 Receptors: Structure and Function”

“…Among the P2X receptors, P2X7 has attracted increasing interest in the field of inflammation and/or immune response as well as in cancer. Rivas-Yanez et al reviewed the role of P2X7 in maturation and migration of antigen-presenting dendritic cells, activation and migration of naïve T cells, inflammasome activation, cytokine secretion, and apoptosis induction [ 16 ]. Panicucci et al explored the interactions between the immune system and muscle regeneration.…”