title: Mechanisms of cyclic nucleotide phosphodiesterases in modulating T cell responses in murine graft-versus-host disease.
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.
authors.affiliation: Institute for Immunology, Johannes Gutenberg-University Medical Center, Mainz, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Weber
authors.forename: Corinna
authors.initials: C
authors.lastname: Lupp
authors.forename: Pamela
authors.initials: P
authors.lastname: Stein
authors.forename: Andreas
authors.initials: A
authors.lastname: Kreft
authors.forename: Tobias
authors.initials: T
authors.lastname: Bopp
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Wehler
authors.forename: Edgar
authors.initials: E
authors.lastname: Schmitt
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Schild
authors.forename: Markus P
authors.initials: MP
authors.lastname: Radsak
mesh_terms: D000208:Acute Disease; D000818:Animals; D002450:Cell Communication / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism; D006086:Graft vs Host Disease / Q000201:enzymology* / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009712:Nucleotides, Cyclic / Q000378:metabolism*; D010641:Phenotype; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D020889:Rolipram / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000276:immunology*
chemical_list: D009712:Nucleotides, Cyclic; D010727:Phosphoric Diester Hydrolases; D020889:Rolipram