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      A CD38/CD203a/CD73 ectoenzymatic pathway independent of CD39 drives a novel adenosinergic loop in human T lymphocytes

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          Abstract

          The tumor microenvironment is characterized by of high levels of extracellular nucleotides that are metabolized through the dynamic and sequential action of cell surface enzymes (ectoenzymes). These ectoenzymes operate according to their spatial arrangement, as part of (1) continuous (molecules on the same cell) or (2) discontinuous (molecules on different cells) pathways, the latter being facilitated by restricted cellular microenvironment. The outcome of this catabolic activity is an increase in the local concentration of adenosine, a nucleoside involved in the control of inflammation and immune responses. The aim of the work presented here was to demonstrate that a previously unexplored enzymatic pathway may be an alternate route to produce extracellular adenosine. Our data show that this new axis is driven by the nucleotide-metabolizing ectoenzymes CD38 (an NAD + nucleosidase), the ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1, also known as CD203a or PC-1) and the 5′ ectonucleotidase (5′-NT) CD73, while bypassing the canonical catabolic pathway mediated by the nucleoside tri- and diphosphohydrolase (NTPDase) CD39. To determine the relative contributions of these cell surface enzymes to the production of adenosine, we exploited a human T-cell model allowing for the modular expression of the individual components of this alternative pathway upon activation and transfection. The biochemical analysis of the products of these ectoenzymes by high-performance liquid chromatography (HPLC) fully substantiated our working hypothesis. This newly characterized pathway may facilitate the emergence of an adaptive immune response in selected cellular contexts. Considering the role for extracellular adenosine in the regulation of inflammation and immunogenicity, this pathway could constitute a novel strategy of tumor evasion, implying that these enzymes may represent ideal targets for antibody-mediated therapy.

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          Most cited references56

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          Adenosine receptors: therapeutic aspects for inflammatory and immune diseases.

          Adenosine is a key endogenous molecule that regulates tissue function by activating four G-protein-coupled adenosine receptors: A1, A2A, A2B and A3. Cells of the immune system express these receptors and are responsive to the modulatory effects of adenosine in an inflammatory environment. Animal models of asthma, ischaemia, arthritis, sepsis, inflammatory bowel disease and wound healing have helped to elucidate the regulatory roles of the various adenosine receptors in dictating the development and progression of disease. This recent heightened awareness of the role of adenosine in the control of immune and inflammatory systems has generated excitement regarding the potential use of adenosine-receptor-based therapies in the treatment of infection, autoimmunity, ischaemia and degenerative diseases.
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            Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology.

            The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR. These reaction products are essential for the regulation of intracellular Ca(2+), the most ancient and universal cell signaling system. The entire family of enzymes controls complex processes, including egg fertilization, cell activation and proliferation, muscle contraction, hormone secretion, and immune responses. Over the course of evolution, the molecules have developed the ability to interact laterally and frontally with other surface proteins and have acquired receptor-like features. As detailed in this review, the loss of CD38 function is associated with impaired immune responses, metabolic disturbances, and behavioral modifications in mice. CD38 is a powerful disease marker for human leukemias and myelomas, is directly involved in the pathogenesis and outcome of human immunodeficiency virus infection and chronic lymphocytic leukemia, and controls insulin release and the development of diabetes. Here, the data concerning diseases are examined in view of potential clinical applications in diagnosis, prognosis, and therapy. The concluding remarks try to frame all of the currently available information within a unified working model that takes into account both the enzymatic and receptorial functions of the molecules.
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              Regulatory T cells: how do they suppress immune responses?

              Regulatory T cells (Tregs), either natural or induced, suppress a variety of physiological and pathological immune responses. One of the key issues for understanding Treg function is to determine how they suppress other lymphocytes at the molecular level in vivo and in vitro. Here we propose that there may be a key suppressive mechanism that is shared by every forkhead box p3 (Foxp3)(+) Treg in vivo and in vitro in mice and humans. When this central mechanism is abrogated, it causes a breach in self-tolerance and immune homeostasis. Other suppressive mechanisms may synergistically operate with this common mechanism depending on the environment and the type of an immune response. Further, Treg-mediated suppression is a multi-step process and impairment or augmentation of each step can alter the ultimate effectiveness of Treg-mediated suppression. These findings will help to design effective ways for controlling immune responses by targeting Treg suppressive functions.
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                Author and article information

                Journal
                Oncoimmunology
                Oncoimmunology
                ONCI
                Oncoimmunology
                Landes Bioscience
                2162-4011
                2162-402X
                01 September 2013
                26 September 2013
                26 September 2013
                : 2
                : 9
                : e26246
                Affiliations
                [1 ]Laboratory of Immunogenetics; Department of Medical Sciences; University of Torino; Torino, Italy
                [2 ]Research Center for Experimental Medicine; University of Torino; Torino, Italy
                [3 ]Transplantation Immunology; ”Città della Salute e della Scienza” Hospital; Torino, Italy
                [4 ]PhD Program on “Biomedical Science and Human Oncology”; University of Torino; Torino, Italy
                [5 ]Department of Experimental Medicine; Section of Biochemistry and CEBR; University of Genova; Genova, Italy
                [6 ]Human Genetics Foundation; University of Torino; Torino, Italy
                Author notes
                [* ]Correspondence to: Alberto L Horenstein, Email: alberto.horenstein@ 123456unito.it and Fabio Malavasi, Email: fabio.malavasi@ 123456unito.it
                Article
                2013ONCOIMM0216R 26246
                10.4161/onci.26246
                3850273
                24319640
                f3381cc8-1b2c-46a3-99dd-a307fcc9b682
                Copyright © 2013 Landes Bioscience

                This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.

                History
                : 31 July 2013
                : 20 August 2013
                : 21 August 2013
                Categories
                Original Research

                Immunology
                cd203a,cd38,nad+,pc-1,adenosine,ectonucleotidases
                Immunology
                cd203a, cd38, nad+, pc-1, adenosine, ectonucleotidases

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