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.

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Purinergic signalling and immune cells.

There are conflicting data about the frequency and role of regulatory T cells (Tregs) during the course of HIV infection. Peripheral blood of a large cohort of HIV-infected patients (n 131) at different stages of disease, including 15 long-term nonprogressors and 21 elite controllers, was analyzed to determine the frequency and phenotype of Tregs, defined as CD4, CD25 high , CD127 low , FoxP3 high cells. A significantly increased relative frequency of Tregs within the CD4 compartment of HIV patients compared to that of healthy controls (P 0.05). The loss of absolute Treg numbers coincided with rising markers of immune activation (P < 0.0006). The initiation of antiviral therapy significantly increased absolute Treg numbers (P < 0.0031). We find that the expression of CD39, a newly defined ectonucleotidase with immunomodulatory functions on Tregs, correlated with progressive HIV disease, HIV viral load, and immune activation. Of note, when tested in peripheral blood mononuclear cells of healthy volunteers, the in vitro capacity to suppress T-cell proliferation was limited to CD4, CD25 high , CD39 T cells. Interestingly, Tregs of elite controllers exhibited not only the highest expression of CCR5, CTLA-4, and ICOS but also the lowest level of CD39. The data presented here reconcile the seemingly contradictory results of previous studies looking at Tregs in HIV and highlight the complexity of Treg-mediated immunoregulation during human viral infections.

Comprehensive analysis of frequency and phenotype of T regulatory cells in HIV infection: CD39 expression of FoxP3+ T regulatory cells correlates with progressive disease.

Extracellular adenosine 5'-triphosphate (ATP) acts on many immune cells to promote inflammation. Conversely, the ATP metabolite adenosine is mainly an anti-inflammatory molecule. The ecto-enzymes CD39 and CD73 can dephosphorylate extracellular ATP to adenosine, thereby controlling this important pathway of immune modulation. Despite their established roles in the immune system, little is known of how CD39 and CD73 are themselves regulated. Recent data have shown that CD73 expression and adenosine generation are up-regulated by transforming growth factor-β, depending on the cytokine content of the local microenvironment. We review here these recent findings and discuss their implications in disease.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2249.2012.04623.x

CD73 and adenosine generation in the creation of regulatory microenvironments.

The elaboration of an effective immune response against pathogenic microbes such as viruses, intracellular bacteria or protozoan parasites relies on the recognition of microbial products called pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs). Ligation of the PRRs leads to synthesis and secretion of pro-inflammatory cytokines and chemokines. Infected cells and other stressed cells also release host-cell derived molecules, called damage-associated molecular patterns (DAMPs, danger signals, or alarmins), which are generic markers for damage. DAMPs are recognized by specific receptors on both immune and nonimmune cells, which, depending on the target cell and the cellular context, can lead to cell differentiation or cell death, and either inflammation or inhibition of inflammation. Recent research has revealed that DAMPs and PAMPs synergize to permit secretion of pro-inflammatory cytokines such as interleukin-1β (IL-1β): PAMPs stimulate synthesis of pro-IL-1β, but not its secretion; while DAMPs can stimulate assembly of an inflammasome containing, usually, a Nod-like receptor (NLR) member, and activation of the protease caspase-1, which cleaves pro-IL-1β into IL-1β, allowing its secretion. Other NLR members do not participate in formation of inflammasomes but play other essential roles in regulation of the innate immune response.

http://biomedj.cgu.edu.tw/pdfs/2012/35/6/images/BiomedJ_2012_35_6_437_104408.pdf

Ambika Sharma

Papers

Adenosine: an endogenous modulator of innate immune system with therapeutic potential.