Mitochondrial Dysfunction, Depleted Purinergic Signaling, and Defective T Cell Vigilance and Immune Defense

Abstract

T cell suppression in sepsis is a well-known phenomenon; however, the underlying mechanisms are not fully understood. Previous studies have shown that T cell stimulation up-regulates mitochondrial adenosine triphosphate (ATP) production to fuel purinergic signaling mechanisms necessary for adequate T cell responses. Here we show that basal mitochondrial ATP production, ATP release, and stimulation of P2X1 receptors represent a standby purinergic signaling mechanism that is necessary for antigen recognition. Inhibition of this process impairs T cell vigilance and the ability of T cells to trigger T cell activation, up-regulate mitochondrial ATP production, and stimulate P2X4 and P2X7 receptors that elicit interleukin 2 production and T cell proliferation. T cells of patients with sepsis lack this standby purinergic signaling system owing to defects in mitochondrial function, ATP release, and calcium signaling. These defects impair antigen recognition and T cell function and are correlated with sepsis severity. Pharmacological targeting of these defects may improve T cell function and reduce the risk of sepsis.

Cutting off the power: inhibition of leukemia cell growth by pausing basal ATP release and P2X receptor signaling?

“…Recently, other evidence has emerged in support of a similar role for mitochondria in tumorigenesis [35][36][37]. We previously reported that mitochondria are central components of the purinergic signaling mechanisms that regulate immune cell functions [13,17,38,39]. Our current results show that highly active mitochondria in Jurkat cells upregulate the purinergic signaling processes that regulate cell metabolism and promote the proliferation of Jurkat cells.…”

“…They are not inactive but maintain a level of vigilance that allows them to detect and respond to antigens in their environment. We have recently shown that unstimulated T cells maintain vigilance via a basal purinergic feedback mechanism that involves low-level mitochondrial activity and ATP production to activate P2X receptors and maintain cellular Ca 2+ homeostasis [17]. In the present study, we found that this basal purinergic signaling mechanism is disturbed in Jurkat cells, resulting in the release of large amounts of ATP that promote proliferation without the need for TCR/CD28 stimulation.…”

“…However, unstimulated T cells also release ATP, albeit at a lower rate than stimulated cells [22]. We found that this continuous basal ATP release feeds a basal purinergic feedback loop that maintains T cell vigilance and the ability of T cells to rapidly respond to external stimuli [17]. Therefore, we wondered whether excessive activity of this basal purinergic feedback mechanism is associated with the unchecked proliferation of leukemia cells.…”

“…Measurements of mitochondrial membrane potential, ROS production, and mitochondrial mass Jurkat cells or primary CD4 + T cells were stained with DHR123 (10 μM), TMRE (100 nM), or MitoTracker Green (50 nM) for 15 min at 37°C, and mitochondrial membrane potential, ROS production, and mitochondrial mass were measured using a FACScalibur flow cytometer (BD Biosciences, San Diego, CA) as previously described [17]. In some experiments, Jurkat cells were treated with inhibitors of P2X receptors at the indicated concentrations for 10 min prior to staining with DHR123 or TMRE.…”

Regulation of the T Cell Response by CD39

“…Pannexins are conserved transmembrane channels that allow the passage of ions and small molecules. Pannexin 1 channels participate in the release of ATP from activated T cells and dendritic cells (DCs) to the extracellular medium (2, 8–10). Pannexins have also been linked to ATP release during apoptosis (11, 12).…”