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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)

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