P2X7 is expressed on human innate‐like T lymphocytes and mediates susceptibility to ATP‐induced cell death

Abstract

Extracellular ATP activates the P2X7 receptor, leading to inflammasome activation and release of pro-inflammatory cytokines in monocytes. However, a detailed analysis of P2X7 receptor expression and function in the human T cell compartment has not been reported. Here, we used a P2X7-specific nanobody to assess cell membrane expression and function of P2X7 on peripheral T lymphocyte subsets. The results show that innate-like T cells, which effectively react to innate stimuli by secreting high amounts of pro-inflammatory cytokines, have the highest expression of P2X7 in the human T cell compartment. Using Tγδ cells as example for an innate-like lymphocyte population, we demonstrate that these cells are more sensitive to P2X7 receptor activation than conventional T cells, affecting fundamental cellular mechanisms like calcium signaling and ATP-induced cell death. The increased susceptibility of innate-like T cells to P2X7-mediated cell death provides a mechanism to control their homeostasis under inflammatory conditions. Understanding the expression and function of P2X7 on human immune cells is essential to assume the benefits and consequences of newly developed P2X7-based therapeutic approaches.

Adenosine triphosphate induced cell death: Mechanisms and implications in cancer biology and therapy

“…Native-like T cells effectively respond to innate stimuli by secreting a multitude of pro-inflammatory cytokines, and human T cell compartments exhibit the highest expression of the P2X7R. Within the innate lymphoid population, Tγδ cells demonstrate heightened sensitivity to P2X7R activation compared to conventional T cells, influencing fundamental cellular mechanisms such as calcium signaling and AICD[ 36 ]. Neuroinflammation is positively linked to P2X7R activation through risk-associated molecular patterns, with eATP being the most prominent among them.…”

Elucidating the molecular basis of ATP-induced cell death in breast cancer: Construction of a robust prognostic model

“…Nonetheless, several overarching mechanisms have been revealed. First, the activation of purinergic receptors, particularly the P2X purinoceptor 7 receptor (P2X7R), has emerged as a pivotal mechanism, triggering a cascade of events culminating in cell death[ 8 , 24 ]. Second, a significant mechanism of AICD involves the elevation of intracellular calcium ion concentration[ 25 , 26 ].…”

“…Second, a significant mechanism of AICD involves the elevation of intracellular calcium ion concentration[ 25 , 26 ]. Moreover, AICD may also be linked to the activation of inflammatory responses[ 8 ]. Finally, the disruption of mitochondrial function is crucial in AICD, with cytochrome c release intimately connected with the activation of apoptosis signaling pathways[ 27 - 29 ].…”

The role of the ATP-adenosine axis in ischemic stroke

“…Mice and humans differ in their expression and regulation of P2 receptors, particularly with respect to P2X7. P2X7 is expressed at lower levels in humans (at least on circulating T cells) than in mice, as shown, for example, for Tregs, which have a very high P2X7 expression in mice, but low expression in humans [ 189 , 190 ]. Compared to rodent P2X7, human P2X7 is around ten times less sensitive to ATP [ 58 ] and requires ATP concentrations in the high micromolar to low millimolar range for activation [ 191 ].…”