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http://doi.org/10.25358/openscience-7577
Autoren: | Weber, Michael Lupp, Corinna Stein, Pamela Kreft, Andreas Bopp, Tobias Wehler, Thomas Schmitt, Edgar Schild, Hansjörg Radsak, Markus |
Titel: | Mechanisms of Cyclic Nucleotide Phosphodiesterases in Modulating T Cell Responses in Murine Graft-versus-Host Disease |
Online-Publikationsdatum: | 19-Aug-2022 |
Erscheinungsdatum: | 2013 |
Sprache des Dokuments: | Englisch |
Zusammenfassung/Abstract: | Graft-versus-host disease (GvHD) is a key contributor to the morbidity and mortality after allogeneic hematopoetic stem cell transplantation (HSCT). Regulatory Foxp3(+) CD4(+) T cells (Treg) suppress conventional T cell activation and can control GvHD. In our previous work, we demonstrate that a basic mechanism of Treg mediated suppression occurs by the transfer of cyclic adenosine monophosphate (cAMP) to responder cells. Whether this mechanism is relevant for Treg mediated suppression of GvHD is currently unknown. To address this question, bone marrow and T cells from C57BL/6 mice were transferred into lethally irradiated BALB/c recipients, and the course of GvHD and survival were monitored. Transplanted recipients developed severe GvHD that was strongly ameliorated by the transfer of donor Treg cells. Towards the underlying mechanisms, in vitro studies revealed that Treg communicated with DCs via gap junctions, resulting in functional inactivation of DC by a metabolic pathway involving cAMP that is modulated by the phosphodiesterase (PDE) 4 inhibitor rolipram. PDE2 or PDE3 inhibitors as well as rolipram suppressed allogeneic T cell activation, indirectly by enhancing Treg mediated suppression of DC activation and directly by inhibiting responder T cell proliferation. In line with this, we observed a cooperative suppression of GvHD upon Treg transfer and additional rolipram treatment. In conclusion, we propose that an important pathway of Treg mediated control of GvHD is based on a cAMP dependent mechanism. These data provide the basis for future concepts to manipulate allogeneic T cell responses to prevent GvHD. |
DDC-Sachgruppe: | 610 Medizin 610 Medical sciences |
Veröffentlichende Institution: | Johannes Gutenberg-Universität Mainz |
Organisationseinheit: | FB 04 Medizin |
Veröffentlichungsort: | Mainz |
ROR: | https://ror.org/023b0x485 |
DOI: | http://doi.org/10.25358/openscience-7577 |
Version: | Published version |
Publikationstyp: | Zeitschriftenaufsatz |
Nutzungsrechte: | CC BY |
Informationen zu den Nutzungsrechten: | https://creativecommons.org/licenses/by/3.0/ |
Zeitschrift: | PLoS one 8 3 |
Seitenzahl oder Artikelnummer: | e58110 |
Verlag: | PLoS |
Verlagsort: | Lawrence, Kan. |
Erscheinungsdatum: | 2013 |
ISSN: | 1932-6203 |
URL der Originalveröffentlichung: | http://dx.doi.org/10.1371/journal.pone.0058110 |
DOI der Originalveröffentlichung: | 10.1371/journal.pone.0058110 |
Enthalten in den Sammlungen: | DFG-OA-Publizieren (2012 - 2017) |
Dateien zu dieser Ressource:
Datei | Beschreibung | Größe | Format | ||
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mechanisms_of_cyclic_nucleoti-20220817162239565.pdf | 681.76 kB | Adobe PDF | Öffnen/Anzeigen |