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Role of regulatory T cells in mucosal immunity
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Treg cells also suppress immune responses through passive or competitive mechanisms. In vitro, Treg cells can outcompete conventional T cells in aggregating around DCs due to high-level expression of the adhesion molecule LFA-1, which binds to ICAM on DCs. Treg cells are also capable of depriving activated conventional T cells of IL-2, which is a critical T-cell growth factor. Treg cells constitutively express the Il2ra (encoding CD25) and Il2rb (CD122) genes and express the high-affinity IL-2R complex at much higher levels than conventional T cells. In contrast to conventional T cells, Treg cells do not secrete IL-2 upon activation and are thus “anergic” because Foxp3 actively represses IL-2 transcription. Thus, Treg cells efficiently consume IL-2, thereby limiting clonal expansion of activated T cells. This “IL-2 consumption” mechanism plays an important role in the regulation of CD8 T-cell responses. For example, Treg cells that cannot bind IL-2 (due to CD122 deficiency) but can transduce IL-2 signals (due to transgenic expression of a constitutively active STAT5 mutant) are impaired in their ability to inhibit the activation of CD8+ T cells but not CD4+ T cells. Treg cells also express CD39 and CD73, both of which are positively regulated by Foxp3 and sequentially degrade immune-stimulatory ATP into immune-regulatory adenosine. It remains unclear, however, whether IL-2 and ATP deprivation are essential for mucosal immune regulation.
Tolerance and autoimmunity
Published in Gabriel Virella, Medical Immunology, 2019
George C. Tsokos, Gabriel Virella
Functional heterogeneity of Tregs: Multiple mechanisms have been ascribed to mouse and human Treg cells that suppress autoreactive T cells: Secretion of immunomodulatory proteins by Treg cells, such as IL-10 and TGFβ, which suppress pro-inflammatory responses. A functional group of Tregs is known as effector (e)Tregs, which produce IL-10, are found in sites of inflammation and are probably responsible for the control of inflammation.Expression of CD80 and CD86 and increased release of the immunosuppressive enzyme, indoleamine-2,3-dioxygenase (IDO) can result in the conversion of dendritic cells to tolerogenic cells.High expression of the ectoenzymes CD39 and CD73 converts ATP to AMP (CD39) and AMP to adenosine (CD73), which is a strong suppressor molecule after it binds to cells expressing adenosine receptors.
Endothelium
Published in Neil Herring, David J. Paterson, Levick's Introduction to Cardiovascular Physiology, 2018
Neil Herring, David J. Paterson
The endothelial lining of blood vessels is now recognized to be central to preventing thrombosis in undamaged vessels by several mechanisms (Figure 9.11):It presents a physical barrier that separates platelets and coagulation factors in the blood from stimulatory collagen in the subendothelial layers of the blood vessel.Secretion of heparan sulphate on the luminal surface activates antithrombin III and prevents the activation of the clotting factors.Powerful inhibitors of platelet activation are synthesized. PGI2 and NO act synergistically to prevent the increase in intra-platelet Ca2+ essential for activation.The enzyme CD39 is expressed on the luminal surface to convert the platelet activator, ADP, to inactive AMP.Tissue plasminogen activator (tPA) is released to convert plasminogen to plasmin, which cleaves fibrin strands, earning tPA the title of ‘clot-buster’.
Antiplatelet therapy for coronary artery disease in 2023: current status and future prospects
Published in Expert Review of Cardiovascular Therapy, 2023
Rishi Chandiramani, Alessandro Spirito, James W. Johnson, Adhya Mehta, Birgit Vogel, Robert T. Faillace, Roxana Mehran
Glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors are potent inhibitors of platelet aggregation that are administered intravenously. In the past, use of these agents was widespread in patients presenting with ACS; indeed, GPIIb/IIIa inhibitors enable rapid inhibition of platelet aggregation until the full effect of oral antiplatelet agents is achieved. In recent years, however, the development of rapidly acting P2Y12 inhibitors and increased awareness about the high rates and prognostic impact of bleeding after administration of GPIIb/IIIa inhibitors have led to a progressive decrease in the use of these agents. Current guidelines recommend using GPIIb/IIIa inhibitors only as ‘bailout’ strategy in ACS patients with high thrombotic burden with no-reflow phenomenon or thrombotic complications during PCI, or as a bridge before surgery in patients at very high ischemic risk (e.g. coronary stenting <1 month before surgery) [38,39]. Dose of GPIIb/IIIa inhibitors should be adapted based on concomitant anticoagulation treatment and renal function. New compounds not yet available for clinical use [e.g. revacept (a competitive antagonist to platelet glycoprotein VI), conformation-specific GP inhibitors, outside-in signaling GP inhibitors or platelet-targeted CD39 protein derivatives] may have a limited impact on bleeding rates while providing effective platelet inhibition [40,41].
Fully human anti-CD39 antibody potently inhibits ATPase activity in cancer cells via uncompetitive allosteric mechanism
Published in mAbs, 2020
Bradley N. Spatola, Alana G. Lerner, Clifford Wong, Tracy dela Cruz, Megan Welch, Wanchi Fung, Maria Kovalenko, Karolina Losenkova, Gennady G. Yegutkin, Courtney Beers, John Corbin, Vanessa B. Soros
CD39, encoded by the gene ectonucleoside triphosphate diphosphohydrolase-1 (ENTPD1), is an integral membrane protein that metabolizes extracellular adenosine triphosphate (ATP) and adenosine diphosphate (ADP) to adenosine monophosphate (AMP); AMP is then further converted to adenosine via another ecto-enzyme, ecto-5ʹ-nucleotidase/CD73.1,2 Extracellular adenosine suppresses the immune system via signaling through four adenosine (P1) receptors expressed on immune cells.3 In contrast, extracellular ATP is pro-inflammatory, regulating innate and adaptive immune responses through agonizing various P2X and P2Y receptors ubiquitously expressed on immune cells.4–7 While there are other potential sources of extracellular adenosine,8–10 CD39 appears to be the major extracellular enzyme catabolizing ATP in the tumor microenvironment (TME).11,12
Ectonucleotidase CD39 expression in regional metastases in head and neck cancer
Published in Acta Oto-Laryngologica, 2018
Magis Mandapathil, Mehtap Boduc, Marion Roessler, Christian Güldner, Ute Walliczek-Dworschak, Robert Mandic
CD39 is an integral membrane protein that metabolizes extracellular adenosine triphosphate (ATP) and adenosine diphosphate (ADP) to adenosine monophosphate (AMP), which is the rate-limiting enymatic step in the production of immunsupressive adenosine [9]. Previous studies demonstrated that CD39 is expressed in multiple various cells, including subsets of leukocyte and endothelial cells [10]. In Treg, CD39 was identified as a functional surface marker relating to Treg presence and immunosuppressive capacities [7,8]. Further, CD39 overexpression and dysregulation have been described for multiple human tumors, including HNSCC [11,12]. For example, decreased CD39 mRNA levels appear to be associated with improved survival rates and linked to less invasive tumors in colorectal cancer [13], indicating a potential role of CD39 in the formation of tumor metastases. To date, there has been no comprehensive description of CD39 expression in primary tumors, nor metastatic lymph nodes in patients with HNSCC, and its prognostic role in this disease.