The role of P2 receptors in controlling infections by intracellular pathogens

A growing number of studies have demonstrated the importance of ATPe-signalling via P2 receptors as an important component of the inflammatory response to infection. More recent studies have shown that ATPe can also have a direct effect on infection by intracellular pathogens, by modulating membrane trafficking in cells that contain vacuoles that harbour intracellular pathogens, such as mycobacteria and chlamydiae. A conserved mechanism appears to be involved in controlling infection by both of these pathogens, as a role for phospholipase D in inducing fusion between lysosomes and the vacuoles has been demonstrated. Other P2-dependent mechanisms are most likely operative in the cases of pathogens, such as Leishmania, which survive in an acidic phagolysosomal-like compartment. ATPe may function as a ‘danger signal–that alerts the immune system to the presence of intracellular pathogens that damage the host cell, while different intracellular pathogens have evolved enzymes or other mechanisms to inhibit ATPe-mediated signalling, which should, thus, be viewed as virulence factors for these pathogens

Purinergic signalling and immune cells

This review article provides a historical perspective on the role of purinergic signalling in the regulation of various subsets of immune cells from early discoveries to current understanding. It is now recognised that adenosine 5'-triphosphate (ATP) and other nucleotides are released from cells following stress or injury. They can act on virtually all subsets of immune cells through a spectrum of P2X ligand-gated ion channels and G protein-coupled P2Y receptors. Furthermore, ATP is rapidly degraded into adenosine by ectonucleotidases such as CD39 and CD73, and adenosine exerts additional regulatory effects through its own receptors. The resulting effect ranges from stimulation to tolerance depending on the amount and time courses of nucleotides released, and the balance between ATP and adenosine. This review identifies the various receptors involved in the different subsets of immune cells and their effects on the function of these cells

Coupling of a P2Z-like purinoceptor to a fatty acid-activated K+ channel in toad gastric smooth muscle cells

Extracellular application of ATP generates two whole-cell currents in toad gastric smooth muscle cells: an immediate inward non-selective cation current (due to the activation of a P2X or P2Z-like receptor) and a slowly developing outward K+ current. The inward non-selective cation current depends on the continuous presence of ATP while the outward K+ current can last for minutes after ATP application ceases.In cell-attached patches, application of ATP to the extra-patch membrane can activate K+ channels in the patch indicating that a diffusible cellular messenger may be involved. The characteristics of these K+ channels are similar to those of a previously described fatty acid-activated K+ channel that is also a stretch-activated channel.This whole-cell K+ current can be induced by ATP in the absence of extracellular Ca2+ (with EGTA present to chelate trace amounts). However, the current generated in the presence of extracellular Ca2+ is considerably larger.The pharmacological profiles for the activation of the non-selective cation current and the K+ current are similar, suggesting that the same P2Z-like receptor could be mediating both responses. This type of plasma membrane receptor/channel-channel coupling by a process that does not appear to involve Ca2+ flow through the receptor/channel or a subsequent membrane potential change may be representative of a new class of signalling mechanisms

The role of B7 molecules in the cell contact-mediated suppression of T cell mitogenesis by immunosuppressive macrophages induced with mycobacterial infection

We found previously that immunosuppressive macrophages (Mφs) induced by Mycobacterium intracellulare infection (MI-Mφs) transmitted their suppressor signals to target T cells through cell contact with target T cells. In this study, we examined what kinds of Mφ surface molecules are required for such cell–to–cell interaction. First, it was found that a B7-1-like molecule (B7–1LM) recognizable with one of three test clones of anti-B7-1 monoclonal antibodies (mAbs) was required for expression of the Mφ suppressor activity. Neither anti-B7-2, anti-ICAM-1, nor anti-VCAM-1 mAb blocked the Mφ suppressor activity. Second, MI-Mφs increased the expression of B7–1LM in parallel with the acquisition of the suppressor activity. Moreover, MI-Mφs bound with target T cells in a B7–1LM-dependent fashion. Third, mAb blocking of CTLA-4 on target T cells did not reduce the suppressor activity of MI-Mφs, suggesting the role of a putative molecule on target T cells other than CTLA-4 as the receptor for B7–1LM of MI-Mφs. Fourth, concanavalin A (Con A) stimulation of MI-Mφs was needed for effective cell contact with target T cells and subsequent expression of the suppressor activity of MI-Mφs. Fifth, the Con A-induced increase in the suppressor activity of MI-Mφs was inhibited by KN-62 but not by herbimycin A, H-7, nor H-88, indicating that Con A-induced up-regulation of MI-Mφ function is mediated by calmodulin-dependent protein kinase II or ATP/P2Z receptors, but independent of protein tyrosine kinase, protein kinase C, and protein kinase A. These findings indicate that a B7/CTLA-4-independent mechanism is needed for the transmission of the suppressor signals from MI-Mφs to target T cells