• Dayton Stanton posted an update 2 months, 2 weeks ago

    Intain a long-term Foxp3 expression and suppressive activity, and since they can even acquire a pro-inflammatory phenotype,From among all the Treg mechanisms related to their suppressive capacity, adenosine triphosphate (ATP) metabolism is one that is well documented. In this context, there are two essential players that constitute the CD39/CD73 axis. CD39 or nucleoside triphosphate diphosphohydrolase 1 (NTDPase 1) is an ectoenzyme that hydrolyzes ATP or ADP to AMP (10). This enzyme is expressed by a subpopulation of Treg and, orchestrated together with another ectonucleotidase named AMPase CD73 present on the Treg surface, they are able to process AMP into adenosine (67). Adenosine exerts immune inhibitory effects as discussed in following paragraphs. It is interesting to note that Foxp3 expression is directly related to adenosine production since retroviral transduction of CD4+ CD25- lymphocytes with Foxp3 induced the expression of CD39 (6, 10), a potent inhibitor of cell proliferation and indirect contributor to the high cAMP levels found in Treg via adenosine generation (9). In order to understand the formation of adenosine, we will describe the origin and relevance of ATP, which is the CD39/ CD73 axis substrate. Extracellular ATP is released under hypoxia, inflammatory rstb.2013.0181 responses, metabolic stress, or other types of cell injury. The impact of extracellular ATP on the immune system is critical since its increase induces the activation of the inflammosome and subsequent release of cytokines, such as IL-1 (68, 69), in response to damage-associated molecular patterns (DAMPS) and pathogen-associated molecular patterns (PAMPS) (70). Therefore, extracellular ATP is considered a danger signal liberated by damaged or dying cells that induces pro- and anti-inflammatory signals. In the context of immune chronic activation as in HIV infection, ATP released by activated T cells seems to have an autocrine effect, prolonging activation and IL-2 secretion (71). In contrast to ATP, adenosine exhibits anti-proliferative and inhibitory effects, hence giving to the CD39/CD73 activity an immune suppressive role (10). In fact, it was shown that induced 1940-0640-8-15 Treg expressing CD39+ acquired higher suppressive capacity than CD39neg iTreg (72). Adenosine plays an antagonistic role on Treg compared to non-Treg responses by directly binding to the adenosine 2a receptor (A2AR), consequently inducing the adenylyl cyclase activity and, therefore, increasing the order Entrectinib intracellular cAMP level. ATP removal and A2AR activation elicits inhibitory functions in dendritic cells and activated T-cell subsets, inducing T-cell anergy (73); whereas in Treg, A2AR induces the generation of Foxp3+ Tregs (73) and enhances Treg immunosuppressive mechanisms (74, 75). Summing up, Treg could dampen immune activation as well as induce activated T-cell dysfunction through CD39/CD73 activity. It is interesting to note that a study of CD39/CD73 distribution in Treg and conventional CD4+ T cells showed that even though CD39 is largely expressed on human Treg (CD4+ CD25hiFoxp3+ T cells), CD73 is not so widely expressed and <1 of Treg expressed both ectonucleotidases at their surface (76?8). OneFrontiers in Immunology | http://www.frontiersin.orgMay 2016 | Volume 7 | ArticleL ez-Abente et al.Treg Mechanisms in the Context of HIV Infectionhypothesis is that only few cells capable of hydrolyzing ATP to adenosine are necessary to induce a local suppression and that this pathway must be finely regulated to avoi.