Human adenosine deaminases ADA1 and ADA2 bind to different subsets of immune cells (original) (raw)
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Cytokines regulate membrane adenosine deaminase on human activated lymphocytes
2001
CD26 is a lymphocyte marker that can anchor adenosine deaminase (ADA) on the T cell surface. We found that ADA is regulated by cytokines on the cell surface during T cell activation. By means of flow cytometry, immunofluorescence, and immunoblotting techniques, we found that interleukin (IL)-2 and IL-12 up-regulate ecto-ADA and CD26 expression. In clear contrast, IL-4 led to down-regulation of lymphocyte surface ADA without modifying the level of CD26. Moreover, neither circulating ADA transcription nor mRNA translation was regulated by cytokines. These results, along with absence of total-ADA modulation, the variable amount of ADA found in purified plasma membranes, and the different effect of Brefeldin A on the surface presence of ADA and CD26 indicated that cytokines regulate the translocation of ADA towards the cell surface through a mechanism not involving CD26. Ecto-ADA protected activated lymphocytes from the toxic effects of extracellular adenosine. Therefore, this cell surface ADA control might constitute part of the fine immunoregulatory mechanism of adenosine-mediated signaling through purinergic receptors in leukocytes. J. Leukoc. Biol. 70: 920 -930; 2001.
Journal of immunology (Baltimore, Md. : 1950), 1996
CD26, a T cell activation Ag, also known as dipeptidyl peptidase IV, is directly associated with adenosine deaminase (ADA) on the surface of T cells and T cell lines. In the present study, we examined both the binding of ADA and CD26 and the functional consequences of this interaction. We found that ADA was associated with CD26 on T cell lines lacking either ADA or dipeptidyl peptidase IV enzymatic activity, indicating that the association between dipeptidyl peptidase IV and ADA did not require enzymatic activity. Moreover, using immunoelectron microscopy, we demonstrated that CD26 and ADA co-localized on the cell surface, but not inside cells, suggesting that CD26 did not transport ADA to the surface. In keeping with this observation, we showed that human CD26-transfected murine pre-B cell lines lacking human ADA acquired ADA from an extracellular source. More importantly, adenosine in the absence of cell surface ADA inhibited T cell proliferation and IL-2 production induced by var...
Journal of immunology (Baltimore, Md. : 1950), 1997
CD26, a 110-kDa cell surface glycoprotein, exhibits dipeptidyl peptidase IV enzyme activity and plays an important role in T cell costimulation. In the present study, we examined both the exact adenosine deaminase (ADA) binding domain on CD26 and the functional consequences of mutated CD26 transfectants that were deficient for cell surface ADA. Using CD26 deletion, human-rat swap, and point mutations, we found that the residues of L340, V341, A342, and R343 on the CD26 molecule were essential amino acids for ADA binding. When these amino acids were mutated and transfected into Jurkat cells, the resultant CD26 transfectants expressed only CD26, not ADA, on the cell surface. The amount of IL-2 produced by wild-type and mutated CD26 transfectants was almost the same following stimulation with anti-CD3 plus PMA. However, the mutated CD26 transfectants were much more sensitive to the inhibitory effect of adenosine on IL-2 production than were the wild CD26 transfectants. These data sugge...
Critical Reviews in Immunology
Adenosine deaminase 1 (ADA1) is an enzyme of the purine metabolism whose congenital defect leads to severe combined immunodeficiency (SCID). Although classically considered a cytosolic enzyme, early evidence from work in brain synaptosomes suggested that the enzyme could be an ectoenzyme. In lymphoid cells, ectoenzymatic activity of ADA1 was also found. The obvious role of this enzyme located on the cell surface of lymphocytes and monocytes was to deaminate adenosine, making it less available for uptaking and metabolism, and also for adenosine-receptor activation. Quite unexpectedly, ADA1 was shown to act extraenzymatically. In addition, cell surface ADA1-binding proteins have been identified. Interestingly, the interaction of ADA1 with these anchoring proteins leads to costimulation of T-cell activation. Recent studies performed with professional antigen-presenting cells and T lymphocytes have shown that ADA1 can bridge the two cell types together by a cross-linking established bet...
Adenosine deaminase potentiates the generation of effector, memory, and regulatory CD4+ T cells
Journal of Leukocyte Biology, 2011
By interacting with CD26 on the CD4 ϩ T cell surface and with the AdoR A 2B on the DC surface, ADA triggers a costimulatory signal for human T cells. The aim of this study was to know whether ADA-mediated costimulation plays a role in the differentiation of T cells. The results show that irrespective of its enzymatic activity and dependent on TNF-␣, IFN-␥, and IL-6 action, ADA enhanced the differentiation of CD4 ϩ CD45RA ϩ CD45ROnaïve T cells toward CD4 ϩ CD25 ϩ CD45RO ϩ Teffs and CD4 ϩ CD45RA -CD45RO ϩ memory T cells. Furthermore, ADA potentiated generation of CD4 ϩ CD25 high Foxp3 ϩ Tregs by a mechanism that seems to be mainly dependent on the enzymatic activity of ADA. Interestingly, an ADA-mediated increase on Teff, memory T cell, and Treg generation occurred, not only in cocultures from healthy individuals but also from HIV-infected patients. These data suggest that ADA is a relevant modulator of CD4 ϩ T cell differentiation, even in cells from immunologically compromised individuals.
Journal of Biological Chemistry, 2009
Naturally occurring regulatory T cells (nTreg) are crucial for maintaining tolerance to self and thus preventing autoimmune diseases and allograft rejections. In cancer, Treg down-regulate antitumor responses by several distinct mechanisms. This study analyzes the role the adenosinergic pathway plays in suppressive activities of human nTreg. Human CD4 ؉ CD25 high FOXP3 ؉ Treg overexpress CD39 and CD73, ectonucleotidases sequentially converting ATP into AMP and adenosine, which then binds to A 2a receptors on effector T cells, suppressing their functions. CD4 ؉ CD39 ؉ and CD4 ؉ CD25 high T cells express low levels of adenosine deaminase (ADA), the enzyme responsible for adenosine breakdown, and of CD26, a surface-bound glycoprotein associated with ADA. In contrast, T effector cells are enriched in CD26/ ADA but express low levels of CD39 and CD73. Inhibitors of ectonucleotidase activity (e.g. ARL67156) and antagonists of the A 2a receptor (e.g. ZM241385) blocked Treg-mediated immunosuppression. The inhibition of ADA activity on effector T cells enhanced Treg-mediated immunosuppression. Thus, human nTreg characterized by the presence of CD39 and the low expression of CD26/ADA are responsible for the generation of adenosine, which plays a major role in Treg-mediated immunosuppression. The data suggest that the adenosinergic pathway represents a potential therapeutic target for regulation of immunosuppression in a broad variety of human diseases.
Adenosine and Adenosine Receptors in the Immunopathogenesis and Treatment of Cancer
Journal of cellular physiology, 2017
Tumor cells overcome anti-tumor responses in part through immunosuppressive mechanisms. There are several immune modulatory mechanisms. Among them, adenosine is an important factor which is generated by both cancer and immune cells in tumor microenvironment to suppress anti-tumor responses. Two cell surface expressed molecules including CD73 and CD39 catalyze the generation of adenosine from adenosine triphosphate (ATP). The generation of adenosine can be enhanced under metabolic stress like tumor hypoxic conditions. Adenosine exerts its immune regulatory functions through four different adenosine receptors including A1, A2A, A2B, and A3 which are expressed on various immune cells. Several studies have indicated the overexpression of adenosine generating enzymes and adenosine receptors in various cancers which was correlated with tumor progression. Since the signaling of adenosine receptors enhances tumor progression, their manipulation can be promising therapeutic approach in cance...
Adenosine: An endogenous modulator of innate immune system with therapeutic potential
European Journal of Pharmacology, 2009
Adenosine is a purine nucleoside, which is produced inside the body under metabolic stress like hypoxic conditions, acute or chronic inflammatory tissue insults. The synthesis of adenosine involves the catabolism of adenine nucleotides (ATP, ADP and AMP) by the action of extracellular ectonucleotidases i.e. CD39 or nucleoside triphosphate dephosphorylase (NTPD) and CD73 or 5′-ectonucleotidase. Once adenosine is released in the extracellular environment, it binds to different types of adenosine (i.e. adenosine A 1 , A 2A , A 2B and A 3 receptors) receptors expressed on various innate immune cells [Neutrophils, macrophages, mast cells, dendritic cells and natural killer cells]. Thus, depending on the type of adenosine receptor to which it binds, adenosine modulates innate immune response during various inflammatory conditions [i.e. chronic (cancer, asthma) as well as acute (sepsis, acute lung injury) inflammatory diseases]. This review summarizes the effect of adenosine on innate immunity and the use of adenosine receptor specific agonists or antagonists in various immunologic disorders (asthma, cancer, HIV-1 infection) as future immunomodulatory therapeutics.