Adenosine A2A Receptor Stimulation Inhibits TCR-Induced Notch1 Activation in CD8+T-Cells
Notch receptors signaling is required for optimal T-cell activation and function. T-cell receptor (TCR) engagement can activate Notch receptors in T-cells in a ligand-independent fashion. In this study, we examined the role of adenosine A2A receptor (A2AR) signaling pathway in regulating the activit...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.00162/full |
| _version_ | 1817997533170892800 |
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| author | Claudia Sorrentino Fokhrul Hossain Paulo C. Rodriguez Rosa A. Sierra Antonio Pannuti Stephen Hatfield Barbara A. Osborne Lisa M. Minter Lucio Miele Silvana Morello |
| author_facet | Claudia Sorrentino Fokhrul Hossain Paulo C. Rodriguez Rosa A. Sierra Antonio Pannuti Stephen Hatfield Barbara A. Osborne Lisa M. Minter Lucio Miele Silvana Morello |
| author_sort | Claudia Sorrentino |
| collection | DOAJ |
| description | Notch receptors signaling is required for optimal T-cell activation and function. T-cell receptor (TCR) engagement can activate Notch receptors in T-cells in a ligand-independent fashion. In this study, we examined the role of adenosine A2A receptor (A2AR) signaling pathway in regulating the activity of Notch1 induced by TCR stimulation in CD8+T-cells. A selective A2AR agonist decreased Notch1 protein expression and Notch1 cleavage, and reduced transcripts of Notch1-target genes Hes1 and Myc in activated CD8+T-cells. Inhibition of TCR-induced Notch1 expression by an A2AR agonist was accompanied by increased cAMP concentration and mimicked by forskolin. This effect was associated with reduced IFN-γ and granzyme B production. The effect of an A2AR agonist was abrogated by a selective A2AR antagonist and absent in CD8+T-cells harvested from A2AR−/− mice. Stimulation of A2AR reduced Notch1 receptor levels by inhibiting upstream TCR signals, including ZAP70 phosphorylation, in turn impairing the generation of the active Notch1 intracellular domain (N1ICD). Direct activation of PKC with PMA and ionomycin bypassed A2AR-induced Notch1 inhibition. Overexpression of N1ICD in CD8+T-cells prevented the suppressive effects of an A2AR agonist on proliferation and cytokine release during activation. Our results identify the A2AR signaling pathway as an important regulator of TCR-induced Notch1 receptor activation in CD8+T-cells, and Notch as an important target of the immune suppressive effects of A2AR. We propose a mechanism whereby A2AR impairs CD8 T-cells function through inhibition of Notch1 receptor activation. |
| first_indexed | 2024-04-14T02:39:39Z |
| format | Article |
| id | doaj.art-03798900c2a24384a59550c33bc67f4b |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-14T02:39:39Z |
| publishDate | 2019-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-03798900c2a24384a59550c33bc67f4b2022-12-22T02:17:10ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-02-011010.3389/fimmu.2019.00162430354Adenosine A2A Receptor Stimulation Inhibits TCR-Induced Notch1 Activation in CD8+T-CellsClaudia Sorrentino0Fokhrul Hossain1Paulo C. Rodriguez2Rosa A. Sierra3Antonio Pannuti4Stephen Hatfield5Barbara A. Osborne6Lisa M. Minter7Lucio Miele8Silvana Morello9Department of Pharmacy, University of Salerno, Fisciano, ItalyDepartment of Genetics and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, United StatesH. L. Moffitt Comprehensive Cancer Center, Tampa, FL, United StatesH. L. Moffitt Comprehensive Cancer Center, Tampa, FL, United StatesDepartment of Genetics and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, United StatesNew England Inflammation and Tissue Protection Institute, Northeastern University, Boston, MA, United StatesDepartment of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA, United StatesDepartment of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA, United StatesDepartment of Genetics and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, United StatesDepartment of Pharmacy, University of Salerno, Fisciano, ItalyNotch receptors signaling is required for optimal T-cell activation and function. T-cell receptor (TCR) engagement can activate Notch receptors in T-cells in a ligand-independent fashion. In this study, we examined the role of adenosine A2A receptor (A2AR) signaling pathway in regulating the activity of Notch1 induced by TCR stimulation in CD8+T-cells. A selective A2AR agonist decreased Notch1 protein expression and Notch1 cleavage, and reduced transcripts of Notch1-target genes Hes1 and Myc in activated CD8+T-cells. Inhibition of TCR-induced Notch1 expression by an A2AR agonist was accompanied by increased cAMP concentration and mimicked by forskolin. This effect was associated with reduced IFN-γ and granzyme B production. The effect of an A2AR agonist was abrogated by a selective A2AR antagonist and absent in CD8+T-cells harvested from A2AR−/− mice. Stimulation of A2AR reduced Notch1 receptor levels by inhibiting upstream TCR signals, including ZAP70 phosphorylation, in turn impairing the generation of the active Notch1 intracellular domain (N1ICD). Direct activation of PKC with PMA and ionomycin bypassed A2AR-induced Notch1 inhibition. Overexpression of N1ICD in CD8+T-cells prevented the suppressive effects of an A2AR agonist on proliferation and cytokine release during activation. Our results identify the A2AR signaling pathway as an important regulator of TCR-induced Notch1 receptor activation in CD8+T-cells, and Notch as an important target of the immune suppressive effects of A2AR. We propose a mechanism whereby A2AR impairs CD8 T-cells function through inhibition of Notch1 receptor activation.https://www.frontiersin.org/article/10.3389/fimmu.2019.00162/fulladenosineA2A adenosine receptor (A2AR)Notch1CD8+T-cellsimmunosuppression |
| spellingShingle | Claudia Sorrentino Fokhrul Hossain Paulo C. Rodriguez Rosa A. Sierra Antonio Pannuti Stephen Hatfield Barbara A. Osborne Lisa M. Minter Lucio Miele Silvana Morello Adenosine A2A Receptor Stimulation Inhibits TCR-Induced Notch1 Activation in CD8+T-Cells Frontiers in Immunology adenosine A2A adenosine receptor (A2AR) Notch1 CD8+T-cells immunosuppression |
| title | Adenosine A2A Receptor Stimulation Inhibits TCR-Induced Notch1 Activation in CD8+T-Cells |
| title_full | Adenosine A2A Receptor Stimulation Inhibits TCR-Induced Notch1 Activation in CD8+T-Cells |
| title_fullStr | Adenosine A2A Receptor Stimulation Inhibits TCR-Induced Notch1 Activation in CD8+T-Cells |
| title_full_unstemmed | Adenosine A2A Receptor Stimulation Inhibits TCR-Induced Notch1 Activation in CD8+T-Cells |
| title_short | Adenosine A2A Receptor Stimulation Inhibits TCR-Induced Notch1 Activation in CD8+T-Cells |
| title_sort | adenosine a2a receptor stimulation inhibits tcr induced notch1 activation in cd8 t cells |
| topic | adenosine A2A adenosine receptor (A2AR) Notch1 CD8+T-cells immunosuppression |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2019.00162/full |
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