Adenosine A2A Receptor Stimulation Inhibits TCR-Induced Notch1 Activation in CD8+T-Cells

Frontiers in Immunology
Claudia SorrentinoSilvana Morello

Abstract

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 agonis...Continue Reading

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Citations

May 20, 2020·British Journal of Pharmacology·Kenneth A JacobsonJens Carlsson
Jul 11, 2020·Journal of Cellular Physiology·Sheng WangXiongwen Lv
Mar 13, 2020·Journal of Translational Medicine·Mariaelena CaponePaolo A Ascierto
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Nov 5, 2019·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Natalia EberhardtMaria Pilar Aoki
Apr 16, 2020·Acta Biomaterialia·Waqas NawazZhiwei Wu
Apr 29, 2021·Signal Transduction and Targeted Therapy·Zhao HuangYong Tang
Aug 8, 2021·International Journal of Molecular Sciences·Peter CuthbertsonRonald Sluyter
Jan 23, 2022·Nature Communications·Russell C LevackGary M Winslow

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Methods Mentioned

BETA
transgenic
PMA
PCR
acetylation
flow cytometry
ELISA

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