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Abstract
Adenosine triphosphate (ATP) is known to induce cell death in T lymphocytes at high extracellular concentrations. CD4+ and CD8+ T lymphocytes have a differential response to ATP, which in mice is due to differences in the P2X7 receptor expression levels. By contrast, we observed that the difference in human CD4+ and CD8+ T lymphocyte response toward the synthetic ATP-analog BzATP is not explained by a difference in human P2X7 receptor expression. Rather, the BzATP-induced human P2X7 receptor response in naïve and immune-activated lymphocyte subtypes correlated with the expression of another ATP-binding receptor: the human P2Y11 receptor. In a recombinant expression system, the coexpression of the human P2Y11 receptor counteracted BzATP-induced human P2X7 receptor-driven lactate dehydrogenase release (a marker of cell death) and pore formation independent of calcium signaling. A mutated non-signaling human P2Y11 receptor had a similar human P2X7 receptor-inhibitory effect on pore formation, thus demonstrating that the human P2X7 receptor interference was not caused by human P2Y11 receptor signaling. In conclusion, we demonstrate an important species difference in the ATP-mediated cell death between mice and human cells and show that in human T lymphocytes, the expression of the human P2Y11 receptor correlates with human P2X7 receptor-driven cell death following BzATP stimulation.
Highlights
The adenosine 5'-triphosphate (ATP)-binding receptor P2X7 has been shown to play an important role in the regulation of immune cells [1, 2]
The results showed that human CD4+ T lymphocytes released more lactate dehydrogenase (LDH) than CD8+ T lymphocytes (Figure 1A) after 2 h of incubation with BzATP
This difference is similar to what has been observed for CD4+ and CD8+ T lymphocytes in mice [7, 8]
Summary
The adenosine 5'-triphosphate (ATP)-binding receptor P2X7 has been shown to play an important role in the regulation of immune cells [1, 2]. P2X7 receptor as an important mediator of the programmed cell death termed pyroptosis, which is characterized as an altruistic cell death where cells swell, burst, and die to release cellular content that attracts other immune cells to continue the fight against infections [5]. This type of P2X7 receptor-mediated cell death has been found important in mouse lymphocytes, where it regulates the homeostasis of T lymphocyte subpopulations [6]. ATP resulted in the surface exposure of phosphatidylserine measured by annexin V staining in mouse CD4+ cells, but not in CD8+ cells This effect correlated with the protein level of the P2X7 receptor [8]
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