P2X7 receptor-dependent cell death is modulated during murine T cell maturation and mediated by dual signaling
Mitsutoshi Tsukimoto1, Machiko Maehata, Hitoshi Harada
1School of Pharmaceutical Sciences, University of Shizuoka, Japan.
Abstract:
Extracellular ATP causes apoptosis and/or necrosis of the hemopoietic lineage through the activation of P2X7 receptors. In this study, we investigated P2X7 receptor-mediated cell death during murine T cell maturation. The expression level and activity of P2X7 receptors, as measured by induction of cell death and pore formation, were higher in splenocytes than thymocytes. Flow cytometric analysis revealed that cell shrinkage was induced by activation of the P2X7 receptor in murine lymphocytes and the responding cells were T cells. Splenic T cells were more responsive than their thymic counterpart. These observations indicate that the system of P2X7 receptor-mediated cell death in T cells could be modulated during T cell maturation. Furthermore, decreased extracellular Cl- suppressed ATP-induced cell shrinkage in splenocytes without inhibiting ERK1/2 phosphorylation, which is reported to mediate necrotic cell death. Treatment with U0126 (a MEK inhibitor) suppressed ATP-induced ERK1/2 phosphorylation without inhibiting cell shrinkage. Moreover, decreased extracellular Cl- and treatment with U0126 suppressed ATP-induced cell death. These observations indicate that the activation of P2X7 receptor leads to T cell death by two independent pathways, one of which is cell shrinkage dependent and the other of which involves the phosphorylation of ERK1/2. In conclusion, we demonstrate increasing P2X7 receptor activity during T cell maturation and the existence of two essential pathways in P2X7 receptor-mediated T cell death. Our findings suggest that ATP-induced cell death of peripheral T lymphocytes is important in P2X7 receptor-regulated immune responses.
Insights
P2X7 receptor activity increases during T cell maturation, leading to T cell death via two pathways: cell shrinkage and ERK1/2 phosphorylation. This highlights P2X7 receptor
Area of Science:
- Immunology
- Cell Biology
Background:
- Extracellular ATP signals through P2X7 receptors, inducing apoptosis or necrosis in hematopoietic cells.
- P2X7 receptor activation is implicated in immune responses and lymphocyte function.
Purpose of the Study:
- To investigate P2X7 receptor-mediated cell death during murine T cell maturation.
- To elucidate the mechanisms and pathways involved in P2X7 receptor activation in T cells.
Main Methods:
- Flow cytometry to analyze cell death, cell shrinkage, and ERK1/2 phosphorylation.
- Assessment of P2X7 receptor expression and activity in thymocytes and splenocytes.
- Manipulation of extracellular chloride concentration and MEK inhibition (U0126).
Main Results:
- P2X7 receptor expression and activity were higher in splenic T cells than thymic T cells.
- ATP-induced T cell death involved both cell shrinkage and ERK1/2 phosphorylation via independent pathways.
- Decreased extracellular chloride and MEK inhibition suppressed ATP-induced cell death.
Conclusions:
- P2X7 receptor activity and its role in T cell death increase during T cell maturation.
- ATP-induced T cell death is mediated by two distinct pathways: cell shrinkage-dependent and ERK1/2 phosphorylation-dependent.
- P2X7 receptor-mediated T cell death is crucial for regulating immune responses involving peripheral T lymphocytes.
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