Adenosine can modulate neutrophil bactericidal functions A d

Adenosine can modulate neutrophil bactericidal functions. A dual regulatory effect has been reported for adenosine on phagocytosis. Indeed, the activation of A1 receptors augments this process, while the stimulation of A2A receptors was found to reduce the phagocytic activity of neutrophils [89]. In parallel, adenosine has a differential effect on reactive oxygen species (ROS) generation based on the receptor subtype activated [82]. In particular, the stimulation of A1 receptors induces ROS production from activated neutrophils, whereas the activation of A2A receptors down-regulates ROS generation [88,90]. Agonists for A2B or A3 receptors suppressed stimulus-induced superoxide production in wild type but not in A2B or A3 deficient neutrophils, respectively [91,92]. Of note, besides regulating chemotaxis and ROS generation, A3 receptors mediate the formation of filipodia-like projections [93]. Indeed, the selective A3 receptor agonist 2-Cl-IB-MECA promoted the formation and rapid extension of these structures, thus improving bacterial phagocytosis [93] and chemotaxis [94].
Adenosine receptors and the adaptive immunity T lymphocytes are responsible for the cell-mediated immune response [95]. These Terfenadine can be stimulated by the presentation of antigenic moieties by APCs, such as dendritic cells or macrophages [96]. The presentation of antigenic molecules on the APC surface in conjunction with major histocompatibility proteins (MHC) causes the activation of T cell receptors on lymphocytes [96], therefore eliciting T cell differentiation, cytokine production, and cytotoxic activity [96]. Once activated, T cells orchestrate effector immune cell function by recruiting macrophages, neutrophils, eosinophils, and basophils to sites of infection and inflammation, and by increasing the microbicidal activity and cytokines and chemokine production of these cells [95]. Adenosine receptors can shape various lymphocyte functions [11]. A2A receptors are the most important receptors in regulating lymphocyte activation, where the overall effect is suppressive [97]. A2A receptors inhibit both IL4 and IFN-γ production by both naive CD4+ T cells and Th1 and Th2 cells [[98], [99], [100]]. In addition, A2A receptors upregulate the expression of the negative co-stimulatory molecules cytotoxic T-lymphocyte antigen 4 (CTLA4) and programmed cell death 1 (PD1) and suppress the expression of the positive co-stimulatory molecule CD-40L [101]. In parallel, the activation of A2A receptors inhibited IL2 release in polarized type 1 cytotoxic T (TC1) and TC2 CD8+ cells [102]. A recent paper by Abbott et al. [103] demonstrated a critical role of A2A receptors in maintaining T follicular help cell/T follicular regulatory cell ratios as well as the overall ratio between T to B cells into the germinal centers. Regulatory T (Treg) cells are a specialized sub-lineage of T lymphocytes with a critical role in controlling and suppressing autoreactive T cells [104]. Multiple suppression mechanisms are in place to suppress autoreactive T cells and prevent autoimmunity[104]. In this regard, early studies by Deaglio et al. [105] demonstrated that Tregs are endowed with the CD39/CD73 enzyme axis, which converts extracellular nucleotides into pericellular adenosine in the vicinity of Tregs. This adenosine in turn engages A2A receptors expressed on T effector cells and suppresses their function. Further studies revealed that adenosine produced by Tregs reduced nuclear factor-κB activation in T effector cells via A2A receptor stimulation, thus blunting the release of pro-inflammatory mediators [106]. There is a self-reinforcing loop in the immunosuppressive activity of Tregs, via adenosine generation. That is, A2A receptor engagement on Tregs induces the expansion of these cells, thereby causing additional immunosuppression [107]. Tregs can, also infiltrate tumor tissues, where they create an immunosuppressive niche, which is facilitates cancer onset and development [108]. In this context, it has been observed that Treg cells can release ATP, convert it to adenosine and cause cytotoxic T cell suppression in the local tumor environment [109].