P2X7 receptor expression levels determine lethal effects of a purine based danger signal in T lymphocytes
1Department of Molecular Microbiology, USC/Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA.
Abstract:
Contact of T lymphocytes with nicotinamide adenine dinucleotide (NAD) or ATP causes cell death that requires expression of purinergic receptor P2X(7) (P2X(7)R). T cell subsets differ in their responses to NAD and ATP, which awaits a mechanistic explanation. Here, we show that sensitivity to ATP correlates with P2X(7)R expression levels in CD4 cells, CD8 cells and CD4(+)CD25(+) cells from both C57BL/6 and BALB/c mice. But P2X(7)R ligands do not only induce cell death but also shedding of CD62L. It is shown here that in CD62L(high) T cells, CD62L shedding correlates with low expression of P2X(7)Rs and lower cell death, whereas in CD62L(low) cells P2X(7)R expression and death are higher. The possibility is therefore investigated that P2X(7)Rs induce T cell activation. Experiments show that spontaneous T cell proliferation is somewhat higher in cells expressing P2X(7)Rs, but this effect we suggest is caused by P2X(7)R expression on accessory cells.
Insights
Nicotinamide adenine dinucleotide (NAD) and ATP trigger T cell death via P2X7 receptors. Cell death and CD62L shedding vary between T cell subsets, influenced by P2X7 receptor expression levels.
Area of Science:
- Immunology
- Cell Biology
- Purinergic Signaling
Background:
- T lymphocytes undergo cell death upon contact with nicotinamide adenine dinucleotide (NAD) or adenosine triphosphate (ATP).
- This cell death necessitates the expression of the purinergic receptor P2X7 (P2X7R).
- Existing research indicates differential responses of T cell subsets to NAD and ATP, lacking a clear mechanistic explanation.
Purpose of the Study:
- To investigate the mechanistic basis for differential T cell responses to ATP and NAD.
- To explore the relationship between P2X7 receptor expression, cell death, and CD62L shedding in various T cell subsets.
- To determine if P2X7 receptors play a role in T cell activation.
Main Methods:
- Flow cytometry was used to analyze P2X7 receptor expression and CD62L shedding in different T cell subsets (CD4, CD8, CD4+CD25+).
- Experiments were conducted using both C57BL/6 and BALB/c mouse models.
- Cell proliferation assays were performed to assess the impact of P2X7R expression on T cell activation.
Main Results:
- Sensitivity to ATP correlated with P2X7R expression levels across CD4, CD8, and CD4+CD25+ T cells.
- P2X7R ligands induced both cell death and CD62L shedding.
- CD62L shedding correlated with lower P2X7R expression and reduced cell death in CD62Lhigh T cells, while CD62Llow T cells exhibited higher P2X7R expression and cell death.
Conclusions:
- T cell responses to ATP are modulated by P2X7R expression levels and CD62L shedding.
- The study provides a mechanistic insight into differential T cell subset responses to purinergic ligands.
- While P2X7R expression may influence T cell proliferation, this effect is likely mediated by accessory cells rather than direct T cell activation.
