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Upregulation of Phosphodiesterase 2A Augments T Cell Activation by Changing cGMP/cAMP Cross-Talk

3′,5′-cyclic adenosine monophosphate (cAMP) is well-known for its diverse immunomodulatory properties, primarily inhibitory effects during T cell activation, proliferation, and production of pro-inflammatory cytokines. A decrease in cAMP levels, due to the hydrolyzing activity of phosphodiesterases...

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Autores principales: Kurelic, Roberta, Krieg, Paula F., Sonner, Jana K., Bhaiyan, Gloria, Ramos, Gustavo C., Frantz, Stefan, Friese, Manuel A., Nikolaev, Viacheslav O.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8523859/
https://www.ncbi.nlm.nih.gov/pubmed/34675812
http://dx.doi.org/10.3389/fphar.2021.748798
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author Kurelic, Roberta
Krieg, Paula F.
Sonner, Jana K.
Bhaiyan, Gloria
Ramos, Gustavo C.
Frantz, Stefan
Friese, Manuel A.
Nikolaev, Viacheslav O.
author_facet Kurelic, Roberta
Krieg, Paula F.
Sonner, Jana K.
Bhaiyan, Gloria
Ramos, Gustavo C.
Frantz, Stefan
Friese, Manuel A.
Nikolaev, Viacheslav O.
author_sort Kurelic, Roberta
collection PubMed
description 3′,5′-cyclic adenosine monophosphate (cAMP) is well-known for its diverse immunomodulatory properties, primarily inhibitory effects during T cell activation, proliferation, and production of pro-inflammatory cytokines. A decrease in cAMP levels, due to the hydrolyzing activity of phosphodiesterases (PDE), is favoring inflammatory responses. This can be prevented by selective PDE inhibitors, which makes PDEs important therapeutic targets for autoimmune disorders. In this study, we investigated the specific roles of PDE2A and PDE3B in the regulation of intracellular cAMP levels in different mouse T cell subsets. Unexpectedly, T cell receptor (TCR) activation led to a selective upregulation of PDE2A at the protein level in conventional T cells (Tcon), whereas no changes were detected in regulatory T cells (Treg). In contrast, protein expression of PDE3B was significantly higher in both non-activated and activated Tcon subsets as compared to Treg, with no changes upon TCR engagement. Live-cell imaging of T cells expressing a highly sensitive Förster resonance energy transfer (FRET)-based biosensor, Epac1-camps, has enabled cAMP measurements in real time and revealed stronger responses to the PDE2A inhibitors in activated vs non-activated Tcon. Importantly, stimulation of intracellular cGMP levels with natriuretic peptides led to an increase of cAMP in non-activated and a decrease of cAMP in activated Tcon, suggesting that TCR activation changes the PDE3B-dependent positive to PDE2A-dependent negative cGMP/cAMP cross-talk. Functionally, this switch induced higher expression of early activation markers CD25 and CD69. This constitutes a potentially interesting feed-forward mechanism during autoimmune and inflammatory responses that may be exploited therapeutically.
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spelling pubmed-85238592021-10-20 Upregulation of Phosphodiesterase 2A Augments T Cell Activation by Changing cGMP/cAMP Cross-Talk Kurelic, Roberta Krieg, Paula F. Sonner, Jana K. Bhaiyan, Gloria Ramos, Gustavo C. Frantz, Stefan Friese, Manuel A. Nikolaev, Viacheslav O. Front Pharmacol Pharmacology 3′,5′-cyclic adenosine monophosphate (cAMP) is well-known for its diverse immunomodulatory properties, primarily inhibitory effects during T cell activation, proliferation, and production of pro-inflammatory cytokines. A decrease in cAMP levels, due to the hydrolyzing activity of phosphodiesterases (PDE), is favoring inflammatory responses. This can be prevented by selective PDE inhibitors, which makes PDEs important therapeutic targets for autoimmune disorders. In this study, we investigated the specific roles of PDE2A and PDE3B in the regulation of intracellular cAMP levels in different mouse T cell subsets. Unexpectedly, T cell receptor (TCR) activation led to a selective upregulation of PDE2A at the protein level in conventional T cells (Tcon), whereas no changes were detected in regulatory T cells (Treg). In contrast, protein expression of PDE3B was significantly higher in both non-activated and activated Tcon subsets as compared to Treg, with no changes upon TCR engagement. Live-cell imaging of T cells expressing a highly sensitive Förster resonance energy transfer (FRET)-based biosensor, Epac1-camps, has enabled cAMP measurements in real time and revealed stronger responses to the PDE2A inhibitors in activated vs non-activated Tcon. Importantly, stimulation of intracellular cGMP levels with natriuretic peptides led to an increase of cAMP in non-activated and a decrease of cAMP in activated Tcon, suggesting that TCR activation changes the PDE3B-dependent positive to PDE2A-dependent negative cGMP/cAMP cross-talk. Functionally, this switch induced higher expression of early activation markers CD25 and CD69. This constitutes a potentially interesting feed-forward mechanism during autoimmune and inflammatory responses that may be exploited therapeutically. Frontiers Media S.A. 2021-10-05 /pmc/articles/PMC8523859/ /pubmed/34675812 http://dx.doi.org/10.3389/fphar.2021.748798 Text en Copyright © 2021 Kurelic, Krieg, Sonner, Bhaiyan, Ramos, Frantz, Friese and Nikolaev. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Kurelic, Roberta
Krieg, Paula F.
Sonner, Jana K.
Bhaiyan, Gloria
Ramos, Gustavo C.
Frantz, Stefan
Friese, Manuel A.
Nikolaev, Viacheslav O.
Upregulation of Phosphodiesterase 2A Augments T Cell Activation by Changing cGMP/cAMP Cross-Talk
title Upregulation of Phosphodiesterase 2A Augments T Cell Activation by Changing cGMP/cAMP Cross-Talk
title_full Upregulation of Phosphodiesterase 2A Augments T Cell Activation by Changing cGMP/cAMP Cross-Talk
title_fullStr Upregulation of Phosphodiesterase 2A Augments T Cell Activation by Changing cGMP/cAMP Cross-Talk
title_full_unstemmed Upregulation of Phosphodiesterase 2A Augments T Cell Activation by Changing cGMP/cAMP Cross-Talk
title_short Upregulation of Phosphodiesterase 2A Augments T Cell Activation by Changing cGMP/cAMP Cross-Talk
title_sort upregulation of phosphodiesterase 2a augments t cell activation by changing cgmp/camp cross-talk
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8523859/
https://www.ncbi.nlm.nih.gov/pubmed/34675812
http://dx.doi.org/10.3389/fphar.2021.748798
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