Generation and Accumulation of Immunosuppressive Adenosine by Human CD4+CD25highFOXP3+ Regulatory T Cells

Mandapathil, Magis; Hilldorfer, Benedict B.; Szczepański, Mirosław J.; Czystowska, Malgorzata; Szajnik, Marta; Ren, Jin; Lang, Stephan; Jackson, Edwin K.; Gorelik, Elieser; Whiteside, Theresa L.

doi:10.1074/jbc.m109.047423

Cited by 339 publications

(353 citation statements)

References 43 publications

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“…Binding of Breg-derived ADO to A 2A R on CD4 C Teff increases cAMP levels resulting in a loss of effector function, a mechanism that is also utilized by Treg as shown by us and others. 28 We suspected that 5 0 -AMP, especially when produced in excess by in vitro-activated B cells, might also contribute to suppression of Teff functions, signaling via the A 1 R receptor. However, neither Teff nor Treg proliferation in response to anti-CD3/CD28 Ab plus IL-2 stimulation was inhibited by exogenous 5 0 -AMP tested at a wide dose range in our hands (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Phenotypic and functional characteristics of CD39^highhuman regulatory B cells (Breg)

et al. 2016

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CD39 and CD73 are key enzymes in the adenosine (ADO) pathway. ADO modulates pathophysiological responses of immune cells, including B cells. It has recently emerged that a subpopulation of ADOproducing CD39 C CD73 C B cells has regulatory properties. Here, we define the CD39 high subset of these cells as the major contributor to the regulatory network operated by human B lymphocytes. Peripheral blood B cells were sorted into CD39 neg , CD39 inter and CD39 high subsets. The phenotype, proliferation and IL-10 secretion by these B cells were studied by flow cytometry. 5 0 -AMP and ADO levels were measured by mass spectrometry. Agonists or antagonists of A 1 R, A 2A R and A 3 R were used to study ADO-

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Section: Discussionmentioning

confidence: 99%

Phenotypic and functional characteristics of CD39^highhuman regulatory B cells (Breg)

et al. 2016

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“…The co-expression of these enzymes on immune cells has been demonstrated for activated mouse Treg and Th17 cells, 9,10 but untreated human Tregs in the circulation only express low levels of intracellular CD73. 11 Mouse peritoneal macrophages may also co-express these enzymes, 12 whereas healthy non-activated human blood monocytes and macrophages have abundant expression of CD39 but not CD73 on the cell surface. 13,14 Ectonucleotidase expression can be controlled by the microenvironment; e.g., CD39 expression is regulated by IL-27 in ovarian cancer, 15 while CD73 is upregulated by hypoxia on epithelial cells 16 by TGFb on murine leukocytes 17 and by signal-transducer and activator of transcription-3 (STAT3) activation on murine Th17 cells.…”

Section: Introductionmentioning

confidence: 99%

Prostaglandin E₂-mediated adenosinergic effects on CD14⁺cells: Self-amplifying immunosuppression in cancer

et al. 2017

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CD39 and CD73 are surface-expressed ectonucleotidases that hydrolyze ATP in a highly regulated, serial manner into ADP, AMP and adenosine. The end product, adenosine, has both tumor-promoting and immunosuppressive effects. The aim of this study was to determine CD73 expression on immune cells in pleural effusion (PE) in order to have a better understanding of the immune environment in mesothelioma. PE-or blood-derived CD14 C cells of mesothelioma patients and healthy donors were analyzed by flow cytometry for the expression of CD39 and CD73. CD73-induction was studied by exposure of CD14 C cells to the soluble fraction of PE (sPE), while the signaling mechanism, responsible for CD73 induction, by phosphoflow cytometry and receptor-inhibition studies. We observed CD73 expression on CD14 C cells in PE but not peripheral blood of mesothelioma patients or healthy donors. CD73 expression was inducible on CD14 C cells with sPE, cyclic-AMP (cAMP)-inducers (forskolin and prostaglandin-E 2 (PGE 2 )) and adenosine. Inhibition of PGE 2 receptors or adenosine A 2 receptors blocked CD73-induction by sPE. sPE treatment triggered protein kinase A and p38 activation. However, signal-transducer and activator of transcription 3 (STAT3)-blocking led to enhanced CD73 expression, demonstrating a hitherto unknown negative control of purinergic signaling by STAT3 in CD14 C cells. TNFa production by CD73 C CD14 C cells was significantly impaired in the presence of AMP, confirming immunosuppressive function. Taken together, CD73 expression can be induced by PGE 2 , cAMP or adenosine on human CD14 C cells. We suggest that targeting this autocrine loop is a valid therapeutic approach in mesothelioma that may also enhance immunotherapy.

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“…The expression of CD39 and CD73 has been demonstrated in both mice and human Tregs in different levels [97,98]. These cells expressed functional ectoenzymes that led to adenosine production [31], as well as inhibition of cytokine production and proliferation of conventional T-cells. Interestingly, it was shown that, in humans, the expression of CD39 is proportional to FOXP3 levels [97,99,100].…”

Section: Regulatory T-cells and Adenosinementioning

confidence: 99%

“…In this sense, the suppressive effects of adenosine are largely mediated through A2AAR and A2BAR signaling in immune cells, with a consequent upregulation of cAMP. Indeed, T-cells express high levels of A2AAR, and the use of A2AAR antagonist blocked Treg-mediated immunosuppression [31,108]. In spite of many papers describing the induction of cAMP due to adenosine-related mechanisms, it is important to note that the accumulation of cAMP on target cells also may also be a consequence of PGE2 production by Tregs [109].…”

Section: Regulatory T-cells and Adenosinementioning

confidence: 99%

“…With such a wide distribution, A2AAR has been linked to several processes, including protection against ischemia-reperfusion injury [22], coronary vasodilatation [23], sleep regulation [24], control of inflammation [21], citing but a few biological events related to such receptor. Regarding the immune system, A2AAR signaling influences a myriad of events, including dendritic cell maturation [25]; inhibition of neutrophil phagocytosis and adhesion [26,27]; suppression of proinflammatory response of macrophages [28]; inhibition of inflammatory cytokine production by lymphocytes [29], control of CD8 Tcells cytotoxicity; and modulation of Treg function [30,31]. Recently, it has also been demonstrated that deletion of A2AAR in mice models causes a decline in the number of naive T-cells in the periphery.…”

Section: Adenosine Receptors-a Brief Overviewmentioning

confidence: 99%

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Adenosine production: a common path for mesenchymal stem-cell and regulatory T-cell-mediated immunosuppression

Bravo

Carvalho

Saldanha-Araújo

2016

Purinergic Signalling

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Adenosine is an important molecule that exerts control on the immune system, by signaling through receptors lying on the surface of immune cells. This nucleotide is produced, in part, by the action of the ectoenzymes CD39 and CD73. Interestingly, these proteins are expressed on the cell surface of regulatory T-cells (Tregs) and mesenchymal stromal cells (MSCs)-two cell populations that have emerged as potential therapeutic tools in the field of cell therapy. In fact, the production of adenosine constitutes a mechanism used by both cell types to control the immune response. Recently, great scientific progress was obtained regarding the role of adenosine in the inflammatory environment. In this context, the present review focuses on the advances related to the impact of adenosine production over the immune modulatory activity of Tregs and MSCs, and how this nucleotide controls the biological functions of these cells. Finally, we mention the main challenges and hurdles to bring such molecule to clinical settings.

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Generation and Accumulation of Immunosuppressive Adenosine by Human CD4+CD25highFOXP3+ Regulatory T Cells

Cited by 339 publications

References 43 publications

Phenotypic and functional characteristics of CD39^highhuman regulatory B cells (Breg)

Phenotypic and functional characteristics of CD39^highhuman regulatory B cells (Breg)

Prostaglandin E₂-mediated adenosinergic effects on CD14⁺cells: Self-amplifying immunosuppression in cancer

Adenosine production: a common path for mesenchymal stem-cell and regulatory T-cell-mediated immunosuppression

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Generation and Accumulation of Immunosuppressive Adenosine by Human CD4+CD25highFOXP3+ Regulatory T Cells

Cited by 339 publications

References 43 publications

Phenotypic and functional characteristics of CD39highhuman regulatory B cells (Breg)

Phenotypic and functional characteristics of CD39highhuman regulatory B cells (Breg)

Prostaglandin E2-mediated adenosinergic effects on CD14+cells: Self-amplifying immunosuppression in cancer

Adenosine production: a common path for mesenchymal stem-cell and regulatory T-cell-mediated immunosuppression

Contact Info

Product

Resources

About

Phenotypic and functional characteristics of CD39^highhuman regulatory B cells (Breg)

Phenotypic and functional characteristics of CD39^highhuman regulatory B cells (Breg)

Prostaglandin E₂-mediated adenosinergic effects on CD14⁺cells: Self-amplifying immunosuppression in cancer