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. 2021 Feb 3;11:619458. doi: 10.3389/fphar.2020.619458

FIGURE 4.

FIGURE 4

Schematic exemplification of purinergic receptor/ectonucleotidase cooperation in the activation/inhibition of the adaptive immune response. ATP can be released into the extracellular space via both regulated and non-regulated mechanisms. (A) In T cells, pannexin-1 (panx-1) and P2XRs localize at the immune synapse following T-cell receptor (TCR) engagement. ATP released via panx-1 triggers P2XRs activation leading to increased MAPK signalling and T cell activation. (B) Treg Foxp3+ cells generation and function are inhibited by ATP-mediated P2XRs signalling. Adenosine (ADO) formed by Treg NTPDase1/CD39 and NT5E/CD73 activity causes Treg cells stabilization, by increasing expression of Foxp3 and NTPDase1/CD39, and inhibits T cells responses acting at A2A and A2B adenosine receptors. Finally, Tregs are protected from P2X7R-mediated apoptosis thanks to extracellular ATP scavenging by NTPDase1/CD39 and NT5E/CD73. (C) Non-pathogenic Th17 cells express NTPDase1/CD39 and NT5E/CD73, and, following IL-6 and TGF-β stimulation, secrete IL-10, thus showing the typical Th17 suppressor cell (SupTh17) phenotype. NTPDase1/CD39 expression by Th17 lymphocytes is enhanced following exposure to aryl hydrocarbon receptor (AhR) agonists, such as unconjugated bilirubin (UCB). Enhanced SupTh17 adenosine deaminase (ADA) activity accelerates conversion of adenosine to inosine (INO), which activates the A3 adenosine receptor on mast cells, thus causing degranulation and release of macrophage chemotactic factors. (D) Human peripheral B cells co-express NTPDase1/CD39 and NT5E/CD73. In vitro activation of B lymphocytes co-cultured with T lymphocytes down-regulates NT5E/CD73 expression and inhibits T cell proliferation and T cell-dependent cytokine release. Extracellular adenosine contributes to immunoglobulin (Ig) class switch recombination in human naïve and IgM memory B cells.