br Adenosine receptors and the

Adenosine receptors and the adaptive immunity T lymphocytes are responsible for the cell-mediated immune response [95]. These cells 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 PNU-120596 australia 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]. B lymphocytes are found in blood, lymph nodes, spleen and tonsil and other mucosal tissues [110]. These cells originate in the bone marrow from a common progenitor shared with T, NK, and some DC subsets [111]. Progenitor B cells progress through the early stages of maturation, rearranging heavy- and light-chain genes at the pro- to pre-B cell stage until they express rearranged IgM receptors on the cell surface as immature B cells, at which point they exit the bone marrow to continue maturation in the peripheral immune system [111]. Murine and human B cells have been shown to express all four types of adenosine receptors [112,113], as well as the presence of a complex network of ectoenzymes (nucleotidases, deaminases, kinases) and nucleoside transporters [114,115]. Recently, a review by Przybyła et al. [115] summarized the involvement of the adenosine system in the modulation of B cell functions, pointing out a critical role of adenosine in regulating the development, implantation and maintenance of the plasma cell population in bone marrow for the primary immune response as well as in orchestrating immunoglobulin class switching, a key mechanism of humoral immune response [115]. In particular, it has been observed that unactivated B cells are characterized by a high pericellular concentration of adenosine, whereas once activated these lymphocytes increase their ATP release [115]. The presence of this “ATPergic halo” protects activated B cells from the adenosine-induced inhibitory effect and exerts a proinflammatory role and a stimulatory effect on IgM production [115].